Input: Identification of APC2, a homologue of the adenomatous polyposis coli tumour suppressor.

adenomatous polyposis coli tumour


Input: The adenomatous polyposis coli (APC) tumour-suppressor protein controls the Wnt signalling pathway by forming a complex with glycogen synthase kinase 3beta (GSK-3beta), axin/conductin and betacatenin.

adenomatous polyposis coli (APC) tumour


Input: Complex formation induces the rapid degradation of betacatenin.


Input: In colon carcinoma cells, loss of APC leads to the accumulation of betacatenin in the nucleus, where it binds to and activates the Tcf-4 transcription factor (reviewed in [1] [2]).

colon carcinoma


Input: Here, we report the identification and genomic structure of APC homologues.


Input: Mammalian APC2, which closely resembles APC in overall domain structure, was functionally analyzed and shown to contain two SAMP domains, both of which are required for binding to conductin.


Input: Like APC, APC2 regulates the formation of active betacatenin-Tcf complexes, as demonstrated using transient transcriptional activation assays in APC-/-colon carcinoma cells.

colon carcinoma


Input: Human APC2 maps to chromosome 19p13.


Input: APC and APC2 may therefore have comparable functions in development and cancer.

cancer


Input: A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer.

HNPCC

colorectal cancer


Input: The frequency, origin, and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated.

hereditary non-polyposis cancer syndrome

HNPCC


Input: The mutation (A--> T at nt943 + 3) disrupts the 3 splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported.


Input: Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England, more extensive analysis has reduced the frequency to four of 52 (8%) English HNPCC kindreds analysed.

colorectal cancer

HNPCC


Input: In contrast, the MSH2 mutation was identified in 10 of 20 (50%) separately identified colorectal families from Newfoundland.

colorectal


Input: To investigate the origin of this mutation in colorectal cancer families from England (n = 4), Newfoundland (n = 10), and the United States (n = 3), haplotype analysis using microsatellite markers linked to MSH2 was performed.

colorectal cancer


Input: Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families.


Input: In contrast, a common haplotype was identified at the two flanking markers (CA5 and D2S288) in eight of the Newfoundland families.


Input: These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families.

HNPCC


Input: We calculated age related risks of all, colorectal, endometrial, and ovarian cancers in nt943 + 3 A--> T MSH2 mutation carriers (n = 76) for all patients and for men and women separately.

colorectal, endometrial, and ovarian cancers


Input: For both sexes combined, the penetrances at age 60 years for all cancers and for colorectal cancer were 0.

cancers

colorectal cancer


Input: 86 and 0.


Input: 57, respectively.


Input: The risk of colorectal cancer was significantly higher (p < 0. 01) in males than females (0. 63 v 0. 30 and 0. 84 v 0. 44 at ages 50 and 60 years, respectively).

colorectal cancer


Input: For females there was a high risk of endometrial cancer (0. 5 at age 60 years) and premenopausal ovarian cancer (0. 2 at 50 years).

endometrial cancer

premenopausal ovarian cancer


Input: These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers.

colorectal cancer

colorectal cancer


Input: Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length.

Huntington disease


Input: Age of onset (AO) of Huntington disease (HD) is known to be correlated with the length of an expanded CAG repeat in the HD gene.

Huntington disease

HD

HD


Input: Apolipoprotein E (APOE) genotype, in turn, is known to influence AO in Alzheimer disease, rendering the APOE gene a likely candidate to affect AO in other neurological diseases too.

Alzheimer disease

neurological diseases


Input: We therefore determined APOE genotype and normal CAG repeat length in the HD gene for 138 HD patients who were previously analysed with respect to CAG repeat length.

HD

HD


Input: Genotyping for APOE was performed blind to clinical information.


Input: In addition to highlighting the effect of the normal repeat length upon AO in maternally inherited HD and in male patients, we show that the APOE epsilon2epsilon3 genotype is associated with significantly earlier AO in males than in females.

HD


Input: Such a sex difference in AO was not apparent for any of the other APOE genotypes.


Input: Our findings suggest that subtle differences in the course of the neurodegeneration in HD may allow interacting genes to exert gender specific effects upon AO.

neurodegeneration

HD


Input: Familial deficiency of the seventh component of complement associated with recurrent bacteremic infections due to Neisseria.

Familial deficiency of the seventh component of complement

bacteremic infections due to Neisseria


Input: The serum of a 29-year old woman with a recent episode of disseminated gonococcal infection and a history of meningococcal meningitis and arthritis as a child was found to lack serum hemolytic complement activity.

disseminated gonococcal infection

meningococcal meningitis

arthritis


Input: The seventh component of complement (C7) was not detected by functional or immunochemical assays, whereas other components were normal by hemolytic and immunochemical assessment.


Input: Her fresh serum lacked complement-mediated bactericidal activity against Neisseria gonorrhoeae, but the addition of fresh normal serum or purified C7 restored bactericidal activity as well as hemolytic activity.


Input: The absence of functional C7 activity could not be accounted for on the basis of an inhibitor.

absence of functional C7


Input: Opsonization and generation of chemotactic activity functioned normally.


Input: Complete absence of C7 was also found in one sibling who had the clinical syndrome of meningococcal meningitis and arthritis as a child and in this siblings clinically well eight-year-old son.

Complete absence of C7

meningococcal meningitis

arthritis


Input: HLA histocompatibility typing of the family members did not demonstrate evidence for genetic linkage of C7 deficiency with the major histocompatibility loci.

C7 deficiency


Input: This report represents the first cases of C7 deficiency associated with infectious complications and suggests that bactericidal activity may be important in host defense against bacteremic neisseria infections.

C7 deficiency

bacteremic neisseria infections


Input: Increased incidence of cancer in patients with cartilage-hair hypoplasia.

cancer

cartilage-hair hypoplasia


Input: OBJECTIVE Previous reports have suggested an increased risk of cancer among patients with cartilage-hair hypoplasia (CHH).

cancer

cartilage-hair hypoplasia

CHH


Input: This study was carried out to further evaluate this risk among patients with CHH and their first-degree relatives.

CHH


Input: STUDY DESIGN One hundred twenty-two patients with CHH were identified through 2 countrywide epidemiologic surveys in 1974 and in 1986.

CHH


Input: Their parents and nonaffected siblings were identified through the Population Register Center.


Input: This cohort underwent follow-up for cancer incidence through the Finnish Cancer Registry to the end of 1995.

cancer


Input: RESULTS A statistically significant excess risk of cancer was seen among the patients with CHH (standardized incidence ratio 6. 9, 95% confidence interval 2. 3 to 16), which was mainly attributable to non-Hodgkins lymphoma (standardized incidence ratio 90, 95% confidence interval 18 to 264).

cancer

CHH

non-Hodgkins lymphoma


Input: In addition, a significant excess risk of basal cell carcinoma was seen (standardized incidence ratio 35, 95% confidence interval 7. 2 to 102).

basal cell carcinoma


Input: The cancer incidence among the siblings or the parents did not differ from the average cancer incidence in the Finnish population.

cancer

cancer


Input: CONCLUSIONS This study confirms an increased risk of cancer, especially non-Hodgkins lymphoma, probably attributable to defective immunity, among patients with CHH.

cancer

non-Hodgkins lymphoma

CHH


Input: Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency.

dihydropyrimidine dehydrogenase deficiency


Input: Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype.

Dihydropyrimidine dehydrogenase (DPD) deficiency

autosomal recessive disease


Input: In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD.

DPD deficiency

deficiency of DPD


Input: In this group of patients, 7 different mutations have been identified, including 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14 + 1G > A)] and 4 missense mutations (85T > C, 703C > T, 2658G > A, 2983G > T).


Input: Analysis of the prevalence of the various mutations among DPD patients has shown that the G--> A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed.

DPD


Input: A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations.

convulsive disorders

motor retardation

mental retardation


Input: A clear correlation between the genotype and phenotype has not been established.


Input: An altered beta-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.

clinical abnormalities

DPD deficiency


Input: Fibroblast growth factor homologous factor 2 (FHF2): gene structure, expression and mapping to the Borjeson-Forssman-Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a BFLS-like patient.

Borjeson-Forssman-Lehmann syndrome

BFLS


Input: Borjeson-Forssman-Lehmann syndrome (BFLS) is a syndromal X-linked mental retardation, which maps by linkage to the q26 region of the human X chromosome.

Borjeson-Forssman-Lehmann syndrome

BFLS

X-linked mental retardation


Input: We have identified a male patient with BFLS-like features and a duplication, 46, Y, dup (X) (q26q28), inherited from his phenotypically normal mother.

BFLS


Input: Fluorescence in situ hybridisation using yeast artificial chromosome clones from Xq26 localised the duplication breakpoint to an approximately 400-kb interval in the Xq26.


Input: 3 region between DXS155 and DXS294/DXS730.


Input: Database searches and analysis of available genomic DNA sequence from the region revealed the presence of the fibroblast growth factor homologous factor gene, FHF2, within the duplication breakpoint interval.


Input: The gene structure of FHF2 was determined and two new exons were identified, including a new 5 end exon, 1B.


Input: FHF2 is a large gene extending over approximately 200 kb in Xq26.


Input: 3 and is composed of at least seven exons.


Input: It shows tissue-specific alternative splicing and alternative transcription starts.


Input: Northern blot hybridisation showed highest expression in brain and skeletal muscle.


Input: The FHF2 gene localisation and tissue-specific expression pattern suggest it to be a candidate gene for familial cases of the BFLS syndrome and other syndromal and non-specific forms of X-linked mental retardation mapping to the region.

BFLS syndrome

X-linked mental retardation


Input: Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer.

familial gastric cancer

colorectal cancer


Input: Inherited mutations in the E-cadherin gene (CDH1) were described recently in three Maori kindreds with familial gastric cancer.

familial gastric cancer


Input: Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations.

Familial gastric cancer

gastric cancer


Input: Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences.

familial gastric cancer


Input: Each family contained (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer.

gastric cancer

gastric cancer


Input: Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%).


Input: Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain.


Input: In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years.

gastric and colorectal cancer

gastric cancer

colorectal cancer


Input: We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations.

familial gastric cancer


Input: However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations.

gastric cancers


Input: Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer.

colorectal and other cancers

colorectal cancer


Input: Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.

gastric and colorectal cancers


Input: A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome.

urogenital abnormalities

Denys-Drash syndrome


Input: The Wilms tumor-suppressor gene, WT1, plays a key role in urogenital development, and WT1 dysfunction is implicated in both neoplastic (Wilms tumor, mesothelioma, leukemias, and breast cancer) and nonneoplastic (glomerulosclerosis) disease.

Wilms tumor

WT1 dysfunction

neoplastic

Wilms tumor

mesothelioma

leukemias

breast cancer

nonneoplastic

glomerulosclerosis


Input: The analysis of diseases linked specifically with WT1 mutations, such as Denys-Drash syndrome (DDS), can provide valuable insight concerning the role of WT1 in development and disease.

Denys-Drash syndrome

DDS


Input: DDS is a rare childhood disease characterized by a nephropathy involving mesangial sclerosis, XY pseudohermaphroditism, and/or Wilms tumor (WT).

DDS

nephropathy

mesangial sclerosis

pseudohermaphroditism

Wilms tumor

WT


Input: DDS patients are constitutionally heterozygous for exonic point mutations in WT1, which include mutations predicted to truncate the protein within the C-terminal zinc finger (ZF) region.

DDS


Input: We report that heterozygosity for a targeted murine Wt1 allele, Wt1 (tmT396), which truncates ZF3 at codon 396, induces mesangial sclerosis characteristic of DDS in adult heterozygous and chimeric mice.

mesangial sclerosis

DDS


Input: Male genital defects also were evident and there was a single case of Wilms tumor in which the transcript of the nontargeted allele showed an exon 9 skipping event, implying a causal link between Wt1 dysfunction and Wilms tumorigenesis in mice.

Male genital defects

Wilms tumor

Wt1 dysfunction

Wilms tumorigenesis


Input: However, the mutant WT1 (tmT396) protein accounted for only 5% of WT1 in both heterozygous embryonic stem cells and the WT.


Input: This has implications regarding the mechanism by which the mutant allele exerts its effect.


Input: Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1.

hereditary hemochromatosis


Input: Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by tissue iron deposition secondary to excessive dietary iron absorption.

Hereditary hemochromatosis

HH

autosomal recessive disorder


Input: We recently reported that HFE, the protein defective in HH, was physically associated with the transferrin receptor (TfR) in duodenal crypt cells and proposed that mutations in HFE attenuate the uptake of transferrin-bound iron from plasma by duodenal crypt cells, leading to up-regulation of transporters for dietary iron.

HH


Input: Here, we tested the hypothesis that HFE-/-mice have increased duodenal expression of the divalent metal transporter (DMT1).


Input: By 4 weeks of age, the HFE-/-mice demonstrated iron loading when compared with HFE +/+ littermates, with elevated transferrin saturations (68. 4% vs. 49. 8%) and elevated liver iron concentrations (985 micrograms vs. 381 micrograms).


Input: By using Northern blot analyses, we quantitated duodenal expression of both classes of DMT1 transcripts one containing an iron responsive element (IRE), called DMT1 (IRE), and one containing no IRE, called DMT1 (non-IRE).


Input: The positive control for DMT1 up-regulation was a murine model of dietary iron deficiency that demonstrated greatly increased levels of duodenal DMT1 (IRE) mRNA.

dietary iron deficiency


Input: HFE-/-mice also demonstrated an increase in duodenal DMT1 (IRE) mRNA (average 7. 7-fold), despite their elevated transferrin saturation and hepatic iron content.


Input: Duodenal expression of DMT1 (non-IRE) was not increased, nor was hepatic expression of DMT1 increased.


Input: These data support the model for HH in which HFE mutations lead to inappropriately low crypt cell iron, with resultant stabilization of DMT1 (IRE) mRNA, up-regulation of DMT1, and increased absorption of dietary iron.


Input: Neurophysiologic follow-up of long-term dietary treatment in adult-onset adrenoleukodystrophy.

adrenoleukodystrophy


Input: OBJECTIVE To monitor the effects of dietary treatment in adult-onset adrenoleukodystrophy (ALD) by means of somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs).

adrenoleukodystrophy

ALD


Input: BACKGROUND SEPs and MEPs have proved useful in revealing signs of progressively severe, central dying-back axonopathy in early stages of adult-onset ALD.

dying-back axonopathy

ALD


Input: METHODS Eight patients with adult-onset ALD underwent clinical examination, brain and spine MRI, and SEP and MEP studies before and after 3 years of Lorenzos oil dietary therapy.

ALD


Input: RESULTS Before treatment, brain MRI was normal in five patients.


Input: Three of these patients had pure spinal SEP abnormalities and in the remaining two patients SEPs showed signs of involvement of both the spinal and cerebral somatosensory tracts.

spinal SEP abnormalities


Input: After treatment, the three patients with pure spinal abnormalities showed clinical and neurophysiologic worsening, whereas the two patients with a more advanced stage of disease (exhibited by SEPs) showed substantially unchanged clinical and neurophysiologic features.

spinal abnormalities


Input: The patients with abnormal brain MRI at the onset of treatment showed clinical and neurophysiologic worsening.


Input: CONCLUSIONS Lorenzos oil therapy had no effect on patients with evidence of inflammatory brain lesions.

inflammatory brain lesions


Input: Moreover, in patients without clear signs of inflammatory damage, this treatment does not modify significantly the natural course of the disease.


Input: However, because effective treatments should begin before the onset of severe neurologic symptoms, SEPs and MEPs should be considered to evaluate the effectiveness of other experimental treatments in the patient with a negative brain MRI.


Input: GCH1 mutation in a patient with adult-onset oromandibular dystonia.

oromandibular dystonia


Input: The authors report a mutation in exon 5 of GCH1 in a patient with adult-onset oromandibular dystonia and no obvious family history of dystonia.

oromandibular dystonia

dystonia


Input: The patient responded positively to treatment with L-dopa.


Input: These findings demonstrate that GCH1 mutations must be considered even in patients with dystonic symptoms not typical of dopa-responsive dystonia.

dystonic

dopa-responsive dystonia


Input: Germline mutations of the APC gene in Korean familial adenomatous polyposis patients.

APC

familial adenomatous polyposis


Input: We extensively analyzed genomic DNA and messenger RNA (mRNA) from 62 unrelated Korean patients with familial adenomatous polyposis (FAP) for identification of germline adenomatous polyposis coli (APC) gene mutations.

familial adenomatous polyposis

FAP

adenomatous polyposis coli

APC


Input: We adopted both single-strand conformation polymorphism (SSCP) analysis and a method of analysis involving the reverse transcription-polymerase chain reaction (RT-PCR) followed by a protein truncation test (PTT).


Input: DNA sequencing confirmed all alterations represented by aberrant bands.


Input: Germline mutations were identified in 38 patients (61%).


Input: Nineteen of the detected mutations were presumed to be novel, thus emphasizing the heterogeneity of the mutational spectrum in Korean FAP patients.

FAP


Input: In the initial 48 patients, SSCP analysis was followed by PTT for those patients for whom no detectable mutations were found by SSCP.


Input: Using this combined approach, we identified germline APC gene mutations in 29 of the 48 FAP patients (60%), including 6 patients in whom SSCP analysis failed to distinguish the mutant allele.

APC

FAP


Input: In the 14 later patients, we identified truncating mutations in 9 patients (64%) using PTT only.


Input: Our results confirm that the mutation detection rate with PTT was superior to that with SSCP, and suggest that PTT would be a more practical screening method to detect germline mutations of the APC gene in FAP patients.

APC

FAP


Input: Molecular epidemiology of C9 deficiency heterozygotes with an Arg95Stop mutation of the C9 gene in Japan.

C9 deficiency


Input: Deficiency of the ninth component of human complement (C9) is the most common complement deficiency in Japan, with an incidence of approximately one homozygote in 1000, but is very rare in other countries.

Deficiency of the ninth component of human complement

complement deficiency


Input: Genetic analyses of Japanese C9 deficiency have shown that a C-to-T transition leading to TGA stop codon for Arg95 in exon 4 of the C9 gene (Arg95Stop) is common in Japanese C9 deficiency.

C9 deficiency

C9 deficiency


Input: To determine the prevalence of heterozygous carriers of the Arg95Stop mutation in a Japanese population, we collected DNA samples from 300 individuals in two of the four main islands of Japan.


Input: Heterozygote detection was performed with an allele-specific polymerase chain reaction (PCR) system designed to detect exclusively only one of the normal and mutant alleles, followed by confirmation with PCR/single-strand conformation polymorphism (SSCP) analysis and direct sequencing.


Input: Twenty individuals were heterozygous for the Arg95Stop mutation.


Input: None was homozygous.


Input: The prevalence of carriers of the Arg95Stop mutation was 6.


Input: 7% (20/300).


Input: An estimated frequency (0. 12%) of complete C9 deficiency due to homozygous Arg95Stop mutation was consistent with frequencies determined by serological studies

C9 deficiency


Input: The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells.

hereditary hemochromatosis


Input: HFE is the protein product of the gene mutated in the autosomal recessive disease hereditary hemochromatosis (Feder, J.

autosomal recessive disease hereditary hemochromatosis


Input: N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D.


Input: A., Basava, A., Dormishian, F., Domingo, R.


Input: J., Ellis, M.


Input: C., Fullan, A., Hinton, L.


Input: M., Jones, N.


Input: L., Kimmel, B.


Input: E., Kronmal, G.


Input: S., Lauer, P., Lee, V.


Input: K., Loeb, D.


Input: B., Mapa, F.


Input: A., McClelland, E., Meyer, N.


Input: C., Mintier, G.


Input: A., Moeller, N., Moore, T., Morikang, E., Prasss, C.


Input: E., Quintana, L., Starnes, S.


Input: M., Schatzman, R.


Input: C., Brunke, K.


Input: J., Drayna, D.


Input: T., Risch, N.


Input: J., Bacon, B.


Input: R., and Wolff, R.


Input: R.


Input: (1996) Nat.


Input: Genet.


Input: 13, 399-408).


Input: At the cell surface, HFE complexes with transferrin receptor (TfR), increasing the dissociation constant of transferrin (Tf) for its receptor 10-fold (Gross, C.


Input: N., Irrinki, A., Feder, J. N., and Enns, C. A. (1998) J. Biol. Chem. 273, 22068-22074; Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl.


Input: Acad.


Input: Sci.


Input: U S A 95, 1472-1477).


Input: HFE does not remain at the cell surface, but traffics with TfR to Tf-positive internal compartments (Gross et al., 1998).


Input: Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, we show that the expression of HFE reduces 55Fe uptake from Tf by 33% but does not affect the endocytic or exocytic rates of TfR cycling.


Input: Therefore, HFE appears to reduce cellular acquisition of iron from Tf within endocytic compartments.


Input: HFE specifically reduces iron uptake from Tf, as non-Tf-mediated iron uptake from Fe-nitrilotriacetic acid is not altered.


Input: These results explain the decreased ferritin levels seen in our HeLa cell system and demonstrate the specific control of HFE over the Tf-mediated pathway of iron uptake.


Input: These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in hereditary hemochromatotic individuals lacking functional HFE.

hereditary hemochromatotic


Input: Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.

familial Mediterranean fever


Input: Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis.

Familial Mediterranean fever

FMF

recessive disorder

serositis

synovitis


Input: The FMF gene (MEFV) was cloned recently, and four missense mutations were identified.

FMF


Input: Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel.


Input: Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes.


Input: Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3.


Input: Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations.

FMF


Input: Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation.


Input: Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R.


Input: Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF.

FMF


Input: The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region.


Input: Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.

Autoimmune lymphoproliferative syndrome


Input: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance.

Autoimmune lymphoproliferative syndrome

ALPS

disorder of lymphocyte homeostasis and immunological tolerance


Input: Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis.


Input: Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas.

ALPS


Input: In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody.


Input: Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations.


Input: In cotransfection experiments, Fas constructs with either intra-or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas.


Input: Two missense Fas variants, not restricted to patients with ALPS, were identified.

ALPS


Input: Variant A (-1) T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles.


Input: Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor.

ALPS


Input: Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives.

ALPS


Input: Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations.

ALPS


Input: Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS.

ALPS


Input: Multicentric origin of hemochromatosis gene (HFE) mutations.

hemochromatosis


Input: Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry.

Genetic hemochromatosis

GH


Input: In northwestern Europe, > 80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein.

GH


Input: In a proportion of GH patients, two mutations are present, C282Y and H63D.

GH


Input: The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease.


Input: The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies > 5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent.


Input: The C282Y mutation occurs on a haplotype that extends </= 6 Mb, suggesting that this mutation has arisen during the past 2, 000 years.


Input: The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending </= 700 kb.


Input: Here we report the finding of the H63D and C282Y mutations on new haplotypes.


Input: In Sri Lanka we have found H63D on three new haplotypes and have found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island.


Input: These results suggest that the HFE gene has been the subject of selection pressure.


Input: These selection pressures could be due to infectious diseases, environmental conditions, or other genetic disorders such as anemia.

infectious diseases

genetic disorders

anemia


Input: A retrospective anonymous pilot study in screening newborns for HFE mutations in Scandinavian populations.


Input: We have retrospectively analyzed 837 random anonymized dried blood spot (DBS) samples from neonatal screening programs in Scandinavia for mutations in HFE, the candidate gene for hemochromatosis.

hemochromatosis


Input: We have found C282Y allele frequencies of 2.


Input: 3% (+ 2. 0%) (-1. 3%) in Greenland, 4.


Input: 5% +/-1.


Input: 9% in Iceland, 5.


Input: 1% +/-2.


Input: 3% in the Faeroe Islands, and 8.


Input: 2% +/-2.


Input: 7% in Denmark.


Input: The high prevalence of HFE mutations in Denmark suggests that population screening for the C282Y mutation could be highly advantageous in terms of preventive health care.


Input: Long-term follow-up evaluation of C282Y homozygotes and H63D/C282Y compound heterozygotes will give an indication of the penetrance of the mutations.


Input: Identification of the mutation in the alkaptonuria mouse model.

alkaptonuria


Input: Alkaptonuria (aku), an inborn error of metabolism caused by the loss of homogentisate 1, 2-dioxygenase (HGD), has been described in a mouse model created by ethylnitrosourea mutagenesis but the mutation in these mice has not previously been identified.

Alkaptonuria

aku

inborn error of metabolism


Input: We used RT-PCR to amplify the Hgd cDNA from Hgd (aku)/Hgd (aku) mice.


Input: Two products shorter than the wild-type product were amplified.


Input: Restriction mapping and DNA sequencing were then used to identify the Hgd (aku) mouse mutation, found to be a single base change in a splice donor consensus sequence, causing exon skipping and frame-shifted products.


Input: This base change allowed us to create a non-radioactive genotyping assay for this allele.


Input: Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.

Non-syndromic hearing loss

enlarged vestibular aqueduct

PDS


Input: Enlarged vestibular aqueduct (EVA), known as the most common form of inner ear abnormality, has recently been of particular genetic interest because this anomaly is inherited in a recessive manner.

Enlarged vestibular aqueduct

EVA

inner ear abnormality


Input: The locus for non-syndromic sensorineural hearing loss with EVA has been mapped to the same chromosomal region, 7q31, as the Pendred syndrome locus.

non-syndromic sensorineural hearing loss

EVA

Pendred syndrome


Input: In the present study, seven mutations in the PDS gene (PDS), the gene responsible for Pendred syndrome, have been found in families of non-syndromic sensorineural hearing loss with EVA.

PDS

Pendred syndrome

non-syndromic sensorineural hearing loss

EVA


Input: One family is homozygous, three families are compound heterozygotes, and two families are heterozygous but with no other mutation detected.


Input: The present results provide evidence that mutations in PDS cause both syndromic and non-syndromic hearing loss..

syndromic and non-syndromic hearing loss


Input: Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy


Input: BACKGROUND X-linked adrenoleukodystrophy (ALD) is an inherited disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency.

X-linked adrenoleukodystrophy

ALD

inherited disease

neurologic dysfunction

adrenal insufficiency


Input: The classic form of ALD usually has onset in childhood (childhood cerebral ALD), with rapid neurologic deterioration leading to a vegetative state.

ALD

childhood cerebral ALD

neurologic deterioration


Input: Adult-onset cerebral ALD also presents with rapidly progressive neurologic dysfunction.

cerebral ALD

neurologic dysfunction


Input: Milder phenotypes such as adrenomyeloneuropathy and Addison disease only also have been recognized.

adrenomyeloneuropathy

Addison disease


Input: Despite discovery of the causative gene, a molecular basis for the diverse clinical presentations remains to be elucidated.


Input: OBJECTIVES To conduct mutational analyses in 29 Japanese patients with ALD from 29 unrelated families, to obtain knowledge of the spectrum of mutations in this gene, and to study genotype-phenotype correlations in Japanese patients.

ALD


Input: METHODS The 29 patients comprised 13 patients with childhood cerebral ALD, 11 patients with adult-onset cerebral ALD, and 5 patients with adrenomyeloneuropathy.

childhood cerebral ALD

cerebral ALD

adrenomyeloneuropathy


Input: We conducted detailed mutational analyses of 29 unrelated Japanese patients with ALD by genomic Southern blot analysis and direct nucleotide sequence analysis of reverse transcriptase-polymerase chain reaction products derived from total RNA that was extracted from cultured skin fibroblasts, lymphoblastoid cells, or peripheral blood leukocytes.

ALD


Input: RESULTS Three patients with adult-onset cerebral ALD were identified as having large genomic rearrangements.

cerebral ALD


Input: The remaining 26 patients were identified as having 21 independent mutations, including 12 novel mutations resulting in small nucleotide alterations in the ALD gene.

ALD


Input: Eighteen (69%) of 26 mutations were missense mutations.


Input: Most missense mutations involved amino acids conserved in homologous gene products, including PMP70, mALDRP, and Pxa1p.


Input: The AG dinucleotide deletion at position 1081-1082, which has been reported previously to be the most common mutation in white patients (12%-17%), was also identified as the most common mutation in Japanese patients (12%).


Input: All phenotypes were associated with mutations resulting in protein truncation or subtle amino acid changes.


Input: There were no differences in phenotypic expressions between missense mutations involving conserved amino acids and those involving nonconserved amino acids.


Input: CONCLUSIONS There are no obvious correlations between the phenotypes of patients with ALD and their genotypes, suggesting that other genetic or environmental factors modify the phenotypic expressions of ALD..

ALD

ALD


Input: A common human skin tumour is caused by activating mutations in beta-catenin.

skin tumour


Input: WNT signalling orchestrates a number of developmental programs.


Input: In response to this stimulus, cytoplasmic beta-catenin (encoded by CTNNB1) is stabilized, enabling downstream transcriptional activation by members of the LEF/TCF family.


Input: One of the target genes for beta-catenin/TCF encodes c-MYC, explaining why constitutive activation of the WNT pathway can lead to cancer, particularly in the colon.

cancer


Input: Most colon cancers arise from mutations in the gene encoding adenomatous polyposis coli (APC), a protein required for ubiquitin-mediated degradation of beta-catenin, but a small percentage of colon and some other cancers harbour beta-catenin-stabilizing mutations.

colon cancers

adenomatous polyposis coli

APC

colon and some other cancers


Input: Recently, we discovered that transgenic mice expressing an activated beta-catenin are predisposed to developing skin tumours resembling pilomatricomas.

skin tumours

pilomatricomas


Input: Given that the skin of these adult mice also exhibits signs of de novo hair-follicle morphogenesis, we wondered whether human pilomatricomas might originate from hair matrix cells and whether they might possess beta-catenin-stabilizing mutations.

pilomatricomas


Input: Here, we explore the cell origin and aetiology of this common human skin tumour.

skin tumour


Input: We found nuclear LEF-1 in the dividing tumour cells, providing biochemical evidence that pilomatricomas are derived from hair matrix cells.

tumour

pilomatricomas


Input: At least 75% of these tumours possess mutations affecting the amino-terminal segment, normally involved in phosphorylation-dependent, ubiquitin-mediated degradation of the protein.

tumours


Input: This percentage of CTNNB1 mutations is greater than in all other human tumours examined thus far, and directly implicates beta-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans..

tumours


Input: The Pendred syndrome gene encodes a chloride-iodide transport protein.

Pendred syndrome


Input: Pendred syndrome is the most common form of syndromic deafness and characterized by congenital sensorineural hearing loss and goitre.

Pendred syndrome

syndromic deafness

sensorineural hearing loss

goitre


Input: This disorder was mapped to chromosome 7 and the gene causing Pendred syndrome (PDS) was subsequently identified by positional cloning.

Pendred syndrome

PDS


Input: PDS encodes a putative transmembrane protein designated pendrin.


Input: Pendrin is closely related to a family of sulfate transport proteins that includes the rat sulfate-anion transporter (encoded by Sat-1; 29% amino acid sequence identity), the human diastrophic dysplasia sulfate transporter (encoded by DTD; 32%) and the human sulfate transporter downregulated in adenoma (encoded by DRA; 45%).

diastrophic dysplasia

adenoma


Input: On the basis of this homology and the presence of a slightly modified sulfate-transporter signature sequence comprising its putative second transmembrane domain, pendrin has been proposed to function as a sulfate transporter.


Input: We were unable to detect evidence of sulfate transport following the expression of pendrin in Xenopus laevis oocytes by microinjection of PDS cRNA or in Sf9 cells following infection with PDS-recombinant baculovirus.


Input: The rates of transport for iodide and chloride were significantly increased following the expression of pendrin in both cell systems.


Input: Our results demonstrate that pendrin functions as a transporter of chloride and iodide, but not sulfate, and may provide insight into thyroid physiology and the pathophysiology of Pendred syndrome..

Pendred syndrome


Input: HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis.

hemochromatosis

hemochromatosis


Input: Hereditary hemochromatosis (HH) is a common autosomal recessive genetic disorder of iron metabolism.

Hereditary hemochromatosis

HH

autosomal recessive genetic disorder


Input: The HFE candidate gene encoding an HLA class I-like protein involved in HH was identified in 1996.

HH


Input: Two missense mutations have been described C282Y, accounting for 80% to 90% of HH chromosomes, and H63D, which is associated with a milder form of the disease representing 40% to 70% of non-C282Y HH chromosomes.

HH

HH


Input: We report here on the analysis of C282Y, H63D, and the 193A--> T substitution leading to the S65C missense substitution in a large series of probands and controls.


Input: The results confirm that the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C282Y mutation.

hemochromatosis

HH


Input: In addition, our screening showed that the S65C substitution was significantly enriched in probands with at least one chromosome without an assigned mutation.


Input: This substitution accounted for 7.


Input: 8% of HH chromosomes that were neither C282Y nor H63D.

HH


Input: This enrichment of S65C among HH chromosomes suggests that the S65C substitution is associated with the mild form of hemochromatosis.

HH

hemochromatosis


Input: Germline BRCA1 alterations in a population-based series of ovarian cancer cases.

ovarian cancer


Input: The objective of this study was to provide more accurate frequency estimates of breast cancer susceptibility gene 1 (BRCA1) germline alterations in the ovarian cancer population.

breast cancer

ovarian cancer


Input: To achieve this, we determined the prevalence of BRCA1 alterations in a population-based series of consecutive ovarian cancer cases.

ovarian cancer


Input: This is the first population-based ovarian cancer study reporting BRCA1 alterations derived from a comprehensive screen of the entire coding region.

ovarian cancer


Input: One hundred and seven ovarian cancer cases were analyzed for BRCA1 alterations using the RNase mismatch cleavage assay followed by direct sequencing.

ovarian cancer


Input: Two truncating mutations, 962del4 and 3600del11, were identified.


Input: Both patients had a family history of breast or ovarian cancer.

breast or ovarian cancer


Input: Several novel as well as previously reported uncharacterized variants were also identified, some of which were associated with a family history of cancer.

cancer


Input: The frequency distribution of common polymorphisms was determined in the 91 Caucasian cancer cases in this series and 24 sister controls using allele-specific amplification.

cancer


Input: The rare form of the Q356R polymorphism was significantly (P = 0. 03) associated with a family history of ovarian cancer, suggesting that this polymorphism may influence ovarian cancer risk.

ovarian cancer

ovarian cancer


Input: In summary, our data suggest a role for some uncharacterized variants and rare forms of polymorphisms in determining ovarian cancer risk, and highlight the necessity to screen for missense alterations as well as truncating mutations in this population.

ovarian cancer


Input: Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): implications for therapy.

adrenoleukodystrophy protein deficiency

X-ALD


Input: Inherited defects in the peroxisomal ATP-binding cassette (ABC) transporter adrenoleukodystrophy protein (ALDP) lead to the lethal peroxisomal disorder X-linked adrenoleukodystrophy (X-ALD), for which no efficient treatment has been established so far.

Inherited defects

adrenoleukodystrophy

peroxisomal disorder X-linked adrenoleukodystrophy

X-ALD


Input: Three other peroxisomal ABC transporters currently are known adrenoleukodystrophy-related protein (ALDRP), 70 kDa peroxisomal membrane protein (PMP70) and PMP70-related protein.


Input: By using transient and stable overexpression of human cDNAs encoding ALDP and its closest relative ALDRP, we could restore the impaired peroxisomal beta-oxidation in fibroblasts of X-ALD patients.

X-ALD


Input: The pathognomonic accumulation of very long chain fatty acids could also be prevented by overexpression of ALDRP in immortalized X-ALD cells.


Input: Immunofluorescence analysis demonstrated that the functional replacement of ALDP by ALDRP was not due to stabilization of the mutated ALDP itself.


Input: Moreover, we were able to restore the peroxisomal beta-oxidation defect in the liver of ALDP-deficient mice by stimulation of ALDRP and PMP70 gene expression through a dietary treatment with the peroxisome proliferator fenofibrate.


Input: These results suggest that a correction of the biochemical defect in X-ALD could be possible by drug-induced overexpression or ectopic expression of ALDRP..

X-ALD


Input: Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells.


Input: Germline mutations of the Brca1 tumor suppressor gene predispose women to breast and ovarian cancers.

tumor

breast and ovarian cancers


Input: To study mechanisms underlying BRCA1-related tumorigenesis, we derived mouse embryonic fibroblast cells carrying a targeted deletion of exon 11 of the Brca1 gene.


Input: We show that the mutant cells maintain an intact G1-S cell cycle checkpoint and proliferate poorly.


Input: However, a defective G2-M checkpoint in these cells is accompanied by extensive chromosomal abnormalities.

chromosomal abnormalities


Input: Mutant fibroblasts contain multiple, functional centrosomes, which lead to unequal chromosome segregation, abnormal nuclear division, and aneuploidy.

aneuploidy


Input: These data uncover an essential role of BRCA1 in maintaining genetic stability through the regulation of centrosome duplication and the G2-M checkpoint and provide a molecular basis for the role of BRCA1 in tumorigenesis..


Input: Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia.

autoimmune lymphoproliferative syndrome, type Ia


Input: Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism.

autoimmune lymphoproliferative syndrome

ALPS


Input: We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein.

ALPS


Input: Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking.

ALPS


Input: These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1..

ALPS


Input: Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1, 2 dioxygenase gene (HGO).

alkaptonuria

AKU


Input: We recently showed that alkaptonuria (AKU) is caused by loss-of-function mutations in the homogentisate 1, 2 dioxygenase gene (HGO).

alkaptonuria

AKU


Input: Herein we describe haplotype and mutational analyses of HGO in seven new AKU pedigrees.

AKU


Input: These analyses identified two novel single-nucleotide polymorphisms (INV4 + 31A--> G and INV11 + 18A--> G) and six novel AKU mutations (INV1-1G--> A, W60G, Y62C, A122D, P230T, and D291E), which further illustrates the remarkable allelic heterogeneity found in AKU.

AKU

AKU


Input: Reexamination of all 29 mutations and polymorphisms thus far described in HGO shows that these nucleotide changes are not randomly distributed; the CCC sequence motif and its inverted complement, GGG, are preferentially mutated.


Input: These analyses also demonstrated that the nucleotide substitutions in HGO do not involve CpG dinucleotides, which illustrates important differences between HGO and other genes for the occurrence of mutation at specific short-sequence motifs.


Input: Because the CCC sequence motifs comprise a significant proportion (34. 5%) of all mutated bases that have been observed in HGO, we conclude that the CCC triplet is a mutational hot spot in HGO.


Input: Fabry disease: identification of novel alpha-galactosidase A mutations and molecular carrier detection by use of fluorescent chemical cleavage of mismatches.

Fabry disease


Input: Fabry disease (FD) (angiokeratoma corporis diffusum) is an X-linked inborn error of glycosphingolipid metabolism caused by defects in the lysosomal alpha-galactosidase A gene (GLA).

Fabry disease

FD

angiokeratoma corporis diffusum

X-linked inborn error of glycosphingolipid metabolism


Input: The enzymatic defect leads to the systemic accumulation of neutral glycosphingolipids with terminal alpha-galactosyl moieties.


Input: Clinically, affected hemizygous males have angiokeratoma, severe acroparesthesia, renal failure, and vasculopathy of the heart and brain.

angiokeratoma

severe acroparesthesia

renal failure

vasculopathy of the heart and brain


Input: While demonstration of alpha-galactosidase deficiency in leukocytes is diagnostic in affected males, enzymatic detection of female carriers is often inconclusive, due to random X-chromosomal inactivation, underlining the need of molecular investigations for accurate genetic counseling.

alpha-galactosidase deficiency


Input: By use of chemical cleavage of mismatches adapted to fluorescence-based detection systems, we have characterized the mutations underlying alpha-Gal A deficiency in 16 individuals from six unrelated families with FD.

alpha-Gal A deficiency

FD


Input: The mutational spectrum included five missense mutations (C202W, C223G, N224D, R301Q, and Q327K) and one splice-site mutation [IVS3 G (-1)--> C].


Input: Studies at the mRNA level showed that the latter led to altered pre-mRNA splicing with consequent alteration of the mRNA translational reading frame and generation of a premature termination codon of translation.


Input: By use of this strategy, carrier status was accurately assessed in all seven at-risk females tested, whereas enzymatic dosages failed to diagnose or exclude heterozygosity..


Input: Prenatal diagnosis by FISH in a family with Pelizaeus-Merzbacher disease caused by duplication of PLP gene.

Pelizaeus-Merzbacher disease


Input: A diagnosis of Pelizaeus-Merzbacher disease (MIM 312080) was made in a young boy.

Pelizaeus-Merzbacher disease


Input: No mutation in the coding region of the proteolipid protein (PLP) gene had been found.


Input: The boys maternal aunt came for prenatal diagnosis when 16 + weeks pregnant and carrying a male fetus.


Input: Samples were tested for duplication of the PLP gene, by interphase FISH, in lymphocyte preparations from the proband, his aunt and an amniotic fluid cell preparation from the fetus.


Input: The proband was found to carry the duplication, thus confirming the diagnosis of Pelizaeus Merzbacher disease, but neither the aunt nor the fetus carried a duplication..

Pelizaeus Merzbacher disease


Input: Dominant negative effect of the APC1309 mutation: a possible explanation for genotype-phenotype correlations in familial adenomatous polyposis.

familial adenomatous polyposis


Input: Inactivation of the adenomatous polyposis coli (APC) gene product initiates colorectal tumorigenesis.

adenomatous polyposis coli

APC


Input: Patients with familial APC (FAP) carry germ-line mutations in the APC gene and develop multiple colorectal adenomas and subsequent carcinomas early in life.

familial APC

FAP

APC

colorectal adenomas

carcinomas


Input: The severity of the disease correlates with the position of the inherited APC mutation (genotype-phenotype correlation).

APC


Input: Together with the fact that both germ-line and sporadic APC mutations cluster in the central region of the APC gene, this points to a dominant negative effect of certain APC mutants.

APC

APC

APC


Input: Loss of APC function was recently shown to result in enhanced beta-catenin-/Tcf-mediated transcription in colon epithelial cells.

APC


Input: Here, we provide experimental evidence for a dominant negative effect of APC gene products associated with severe polyposis.

APC

polyposis


Input: Wild-type APC activity in beta-catenin-/Tcf-mediated transcription was strongly inhibited by a mutant APC that is truncated at codon 1309.

APC

APC


Input: In contrast, mutant APC gene products that are associated with attenuated polyposis (codon 386 or 1465) interfered only weakly with wild-type APC activity.

APC

attenuated polyposis

APC


Input: These results suggest a molecular explanation for the genotype-phenotype correlation in FAP patients and support the idea that colorectal tumor growth might be, in part, driven by selection for a mutation in the mutation cluster region..

FAP

colorectal tumor


Input: BRCA1 interacts with components of the histone deacetylase complex.


Input: Germ-line mutations in the BRCA1 tumor-suppressor gene are associated with an increased susceptibility to breast and ovarian cancer.

breast and ovarian cancer


Input: BRCA1 contains a carboxyl-terminal domain (BRCT) that is shared with several other proteins involved in maintaining genome integrity.


Input: In an effort to understand the function of BRCA1, we sought to isolate proteins that interact with the BRCT domain.


Input: Purified BRCT polypeptide was used as a probe to screen a human placenta cDNA expression library by Far Western analysis.


Input: Here we report that BRCA1 interacts in vivo and in vitro with the Rb-binding proteins, RbAp46 and RbAp48, as well as with Rb.


Input: Moreover, the BRCT domain associates with the histone deacetylases HDAC1 and HDAC2.


Input: These results demonstrate that BRCA1 interacts with components of the histone deacetylase complex, and therefore may explain the involvement of BRCA1 in multiple processes such as transcription, DNA repair, and recombination..


Input: Combined genetic deficiency of C6 and C7 in man.

Combined genetic deficiency of C6 and C7


Input: By routine screening of sera, a subject was discovered who showed a sub-total deficiency of C6 and C7.

sub-total deficiency of C6 and C7


Input: No clinical disease was associated with this deficiency which was transmitted through the subjects family as a single genetic characteristic, the C6 deficiency being associated with a silent allele at the structural locus.

C6 deficiency


Input: The propositus was found to have low quantities of an abnormal C6 which was both antigenically deficient and smaller in size than normal C6 (110, 000 daltons compared with 140, 000 daltons) and small quantities of apparently normal C7.


Input: It is concluded that the most likely explanation for this defect is that the subject has a structural mutation in his C6 gene which produces hyopsynthesis not only of C6 but also of the closely linked gene for C7.


Input: These findings suggest the possibility that C6 and C7 may function as a single genetic unit and that the primary transcript copied from the genome includes information for both proteins..


Input: Changes at P183 of emerin weaken its protein-protein interactions resulting in X-linked Emery-Dreifuss muscular dystrophy.

X-linked Emery-Dreifuss muscular dystrophy


Input: Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive muscular dystrophy characterized by early contractures of the elbows, Achilles tendons and spine, slowly progressive muscle wasting and weakness, and cardiomyopathy associated with cardiac conduction defects.

Emery-Dreifuss muscular dystrophy

EDMD

X-linked recessive muscular dystrophy

contractures of the elbows, Achilles tendons and spine

muscle wasting

weakness

cardiomyopathy

cardiac conduction defects


Input: The emerin gene has been mapped to Xq28 and encodes a 34-kDa serine-rich protein, emerin, which has been localized to the nuclear envelope in a wide variety of tissues, including skeletal and cardiac muscle.


Input: Mutations spanning the emerin gene have been identified in patients with EDMD.

EDMD


Input: We present here the effect, on emerin protein expression, of two missense mutations identified in unrelated EDMD patients.

EDMD


Input: These alterations predict the replacement of a proline residue at position 183 with either a histidine or a threonine.


Input: Biochemical analysis has demonstrated that the mobility and expression levels of the mutant forms of emerin are indistinguishable from that of wild-type emerin, but that they have weakened interactions with nuclear lamina components.


Input: In comparison with the usual EDMD phenotype, patients with P183 missense mutations have a later age at onset of first symptoms, elbow contractures, ankle contractures, upper limb weakness and lower limb weakness, but there is no difference for the age at onset of cardiac involvement.

EDMD

elbow contractures

ankle contractures

upper limb weakness

lower limb weakness

cardiac involvement


Input: This is the first report of protein studies on patients with missense mutations resulting in the clinical features of EDMD.

EDMD


Input: These studies demonstrate the importance of proline 183 for the proper structure/function of emerin..


Input: Microdeletions at chromosome bands 1q32-q41 as a cause of Van der Woude syndrome.

Van der Woude syndrome


Input: Van der Woude syndrome (VWS) is an autosomal dominant disorder comprising cleft lip and/or cleft palate and lip pits.

Van der Woude syndrome

VWS

autosomal dominant disorder

cleft lip

cleft palate

lip pits


Input: We reported previously a family whose underlying mutation is a 500-800 kb deletion localized to chromosome bands 1q32-q41 [Sander et al., 1994 Hum Mol Genet 3 576-578].


Input: Along with cleft lip/palate and lip pits, affected relatives exhibit developmental delays, suggesting that the function of a gene nearby may also be disrupted.

cleft lip/palate

lip pits

developmental delays


Input: To further localize the VWS gene we searched for other deletions that cause VWS.

VWS

VWS


Input: An allele loss assay was performed using a novel highly polymorphic marker, D1S3753.


Input: From a panel of 37 unrelated individuals, we detected an allele loss in one family, indicating the presence of a deletion.


Input: In this family, the phenotype in three generations of affected individuals was confined to the cardinal signs of VWS.

VWS


Input: Surprisingly, mapping of the new deletion showed that it extended 0.


Input: 2-1 Mb beyond the proximal breakpoint for the deletion described previously.


Input: No deletions were detected in seven cases of popliteal pterygia syndrome, 76 cases of mixed syndromic forms of cleft lip and palate, and 178 cases of nonsyndromic cleft lip and palate.

popliteal pterygia syndrome

syndromic forms of cleft lip and palate

nonsyndromic cleft lip and palate


Input: Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.

ataxia-telangiectasia


Input: Mutations resulting in defective splicing constitute a significant proportion (30/62 [48%]) of a new series of mutations in the ATM gene in patients with ataxia-telangiectasia (AT) that were detected by the protein-truncation assay followed by sequence analysis of genomic DNA.

ataxia-telangiectasia

AT


Input: Fewer than half of the splicing mutations involved the canonical AG splice-acceptor site or GT splice-donor site.


Input: A higher percentage of mutations occurred at less stringently conserved sites, including silent mutations of the last nucleotide of exons, mutations in nucleotides other than the conserved AG and GT in the consensus splice sites, and creation of splice-acceptor or splice-donor sites in either introns or exons.


Input: These splicing mutations led to a variety of consequences, including exon skipping and, to a lesser degree, intron retention, activation of cryptic splice sites, or creation of new splice sites.


Input: In addition, 5 of 12 nonsense mutations and 1 missense mutation were associated with deletion in the cDNA of the exons in which the mutations occurred.


Input: No ATM protein was detected by western blotting in any AT cell line in which splicing mutations were identified.

ATM


Input: Several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA were also observed, suggesting caution in the interpretation of exon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations..


Input: Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy.

familial hypertrophic cardiomyopathy


Input: We identified the alpha-cardiac actin gene (ACTC) as a novel disease gene in a pedigree suffering from familial hypertrophic cardiomyopathy (FHC).

familial hypertrophic cardiomyopathy

FHC


Input: Linkage analyses excluded all the previously reported FHC loci as possible disease loci in the family studied, with lod scores varying between-2.

FHC


Input: 5 and-6.


Input: 0 0.


Input: Further linkage analyses of plausible candidate genes highly expressed in the adult human heart identified ACTC as the most likely disease gene, showing a maximal lod score of 3.


Input: 6 6.


Input: Mutation analysis of ACTC revealed an Ala295Ser mutation in exon 5 close to 2 missense mutations recently described to cause the inherited form of idiopathic dilated cardiomyopathy (IDC).

idiopathic dilated cardiomyopathy

IDC


Input: Overgrowth of oral mucosa and facial skin, a novel feature of aspartylglucosaminuria.

Overgrowth of oral mucosa and facial skin

aspartylglucosaminuria


Input: Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by deficiency of aspartylglucosaminidase (AGA).

Aspartylglucosaminuria

AGU

lysosomal storage disorder

deficiency of aspartylglucosaminidase


Input: The main symptom is progressive mental retardation.

mental retardation


Input: A spectrum of different mutations has been reported in this disease, one missense mutation (Cys163Ser) being responsible for the majority of Finnish cases.


Input: We were able to examine 66 Finnish AGU patients for changes in the oral mucosa and 44 of these for changes in facial skin.

AGU


Input: Biopsy specimens of 16 oral lesions, 12 of them associated with the teeth, plus two facial lesions were studied histologically.

facial lesions


Input: Immunohistochemical staining for AGA was performed on 15 oral specimens.


Input: Skin was seborrhoeic in adolescent and adult patients, with erythema of the facial skin already common in childhood.

erythema of the facial skin


Input: Of 44 patients, nine (20%) had facial angiofibromas, tumours primarily occurring in association with tuberous sclerosis.

facial angiofibromas

tumours

tuberous sclerosis


Input: Oedemic buccal mucosa (leucoedema) and gingival overgrowths were more frequent in AGU patients than in controls (p < 0. 001).

Oedemic buccal mucosa

leucoedema

gingival overgrowths

AGU


Input: Of 16 oral mucosal lesions studied histologically, 15 represented fibroepithelial or epithelial hyperplasias and were reactive in nature.

oral mucosal lesions

fibroepithelial or epithelial hyperplasias


Input: Cytoplasmic vacuolisation was evident in four.


Input: Immunohistochemically, expression of AGA in AGU patients mucosal lesions did not differ from that seen in corresponding lesions of normal subjects.

AGU

mucosal lesions


Input: Thus, the high frequency of mucosal overgrowth in AGU patients does not appear to be directly associated with lysosomal storage or with alterations in the level of AGA expression.

mucosal overgrowth

AGU


Input: Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene.

Lowe syndrome


Input: The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys.

oculocerebrorenal syndrome of Lowe

OCRL

X-linked disorder

abnormalities of eyes, nervous system, and kidneys


Input: Mutations in the OCRL1 gene have been associated with the disease.


Input: OCRL1 encodes a phosphatidylinositol 4, 5-biphosphate (PtdIns [4, 5] P2) 5-phosphatase.


Input: We have examined the OCRL1 gene in eight unrelated patients with OCRL and have found seven new mutations and one recurrent in-frame deletion.


Input: Among the new mutations, two nonsense mutations (R317X and E558X) and three other frameshift mutations caused premature termination of the protein.


Input: A missense mutation, R483G, was located in the highly conserved PtdIns (4, 5) P2 5-phosphatase domain.


Input: Finally, one frameshift mutation, 2799delC, modifies the C-terminal part of OCRL1, with an extension of six amino acids.


Input: Altogether, 70% of missense mutations are located in exon 15, and 52% of all mutations cluster in exons 11-15.


Input: We also identified two new microsatellite markers for the OCRL1 locus, and we detected a germline mosaicism in one family.


Input: This observation has direct implications for genetic counseling of Lowe syndrome families..

Lowe syndrome


Input: MEFV-Gene analysis in armenian patients with Familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications.

Familial Mediterranean fever


Input: Familial Mediterranean fever (FMF) is a recessively inherited disorder that is common in patients of Armenian ancestry.

Familial Mediterranean fever

FMF

recessively inherited disorder


Input: To date, its diagnosis, which can be made only retrospectively, is one of exclusion, based entirely on nonspecific clinical signs that result from serosal inflammation and that may lead to unnecessary surgery.

serosal inflammation


Input: Renal amyloidosis, prevented by colchicine, is the most severe complication of FMF, a disorder associated with mutations in the MEFV gene.

Renal amyloidosis

FMF


Input: To evaluate the diagnostic and prognostic value of MEFV-gene analysis, we investigated 90 Armenian FMF patients from 77 unrelated families that were not selected through genetic-linkage analysis.

FMF


Input: Eight mutations, one of which (R408Q) is new, were found to account for 93% of the 163 independent FMF alleles, with both FMF alleles identified in 89% of the patients.

FMF

FMF


Input: In several instances, family studies provided molecular evidence for pseudodominant transmission and incomplete penetrance of the disease phenotype.


Input: The M694V homozygous genotype was found to be associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes (P =. 0002 and P =. 006, respectively).

renal amyloidosis

arthritis


Input: The demonstration of both the diagnostic and prognostic value of MEFV analysis and particular modes of inheritance should lead to new ways for management of FMF-including genetic counseling and therapeutic decisions in affected families.


Input: Noninvasive test for fragile X syndrome, using hair root analysis.

fragile X syndrome


Input: Identification of the FMR1 gene and the repeat-amplification mechanism causing fragile X syndrome led to development of reliable DNA-based diagnostic methods, including Southern blot hybridization and PCR.

fragile X syndrome


Input: Both methods are performed on DNA isolated from peripheral blood cells and measure the repeat size in FMR1.


Input: Using an immunocytochemical technique on blood smears, we recently developed a novel test for identification of patients with fragile X syndrome.

fragile X syndrome


Input: This method, also called " antibody test, " uses monoclonal antibodies against the FMR1 gene product (FMRP) and is based on absence of FMRP in patients cells.


Input: Here we describe a new diagnostic test to identify male patients with fragile X syndrome, on the basis of lack of FMRP in their hair roots.

fragile X syndrome


Input: Expression of FMRP in hair roots was studied by use of an FMRP-specific antibody test, and the percentage of FMRP-expressing hair roots in controls and in male fragile X patients was determined.

fragile X


Input: Control individuals showed clear expression of FMRP in nearly every hair root, whereas male fragile X patients lacked expression of FMRP in almost all their hair roots.

fragile X


Input: Mentally retarded female patients with a full mutation showed FMRP expression in only some of their hair roots (< 55%), and no overlap with normal female controls was observed.

Mentally retarded


Input: The advantages of this test are (1) plucking of hair follicles does no appreciable harm to the mentally retarded patient, (2) hairs can be sent in a simple envelope to a diagnostic center, and (3) the result of the test is available within 5 h of plucking.

mentally retarded


Input: In addition, this test enabled us to identify two fragile X patients who did not show the full mutation by analysis of DNA isolated from blood cells..

fragile X


Input: In Swedish families with hereditary prostate cancer, linkage to the HPC1 locus on chromosome 1q24-25 is restricted to families with early-onset prostate cancer.

hereditary prostate cancer

prostate cancer


Input: Prostate cancer clusters in some families, and an estimated 5%-10% of all cases are estimated to result from inheritance of prostate cancer-susceptibility genes.

Prostate cancer


Input: We previously reported evidence of linkage to the 1q24-25 region (HPC1) in 91 North American and Swedish families each with multiple cases of prostate cancer (Smith et al. 1996).

prostate cancer


Input: In the present report we analyze 40 (12 original and 28 newly identified) Swedish families with hereditary prostate cancer (HPC) that, on the basis of 40 markers spanning a 25-cM interval within 1q24-25, have evidence of linkage.

hereditary prostate cancer

HPC


Input: In the complete set of families, a maximum two-point LOD score of 1.


Input: 10 was observed at D1S413 (at a recombination fraction [theta] of. 1), with a maximum NPL (nonparametric linkage) Z score of 1.


Input: 64 at D1S202 (P =. 05).


Input: The evidence of linkage to this region originated almost exclusively from the subset of 12 early-onset (age < 65 years) families, which yielded a maximum LOD score of 2.


Input: 38 at D1S413 (straight theta = 0) and an NPL Z score of 1.


Input: 95 at D1S422 (P =. 03).


Input: Estimates from heterogeneity tests suggest that, within Sweden, as many as 50% of early-onset families had evidence of linkage to the HPC1 region.


Input: These results are consistent with the hypothesis of linkage to HPC1 in a subset of families with prostate cancer, particularly those with an early age at diagnosis.

prostate cancer


Input: Molecular basis of feline beta-glucuronidase deficiency: an animal model of mucopolysaccharidosis VII.

beta-glucuronidase deficiency

mucopolysaccharidosis VII


Input: A family of domestic cats was found that exhibited clinical and biochemical abnormalities consistent with mucopolysaccharidosis VII, an autosomal recessive lysosomal storage disorder caused by beta-glucuronidase deficiency.

mucopolysaccharidosis VII

autosomal recessive lysosomal storage disorder

beta-glucuronidase deficiency


Input: beta-Glucuronidase activity was undetectable in affected cat fibroblasts and restored by retroviral gene transfer of rat beta-glucuronidase cDNA.


Input: beta-Glucuronidase mRNA was normal in affected cat testis by Northern blot analysis.


Input: Normal feline beta-glucuronidase cDNA was cloned and characterized, and amplified from affected cat fibroblasts by reverse transcription coupled polymerase chain reaction.


Input: There was a G-to-A transition in the affected cat cDNA that predicted an E351K substitution, destroyed a BssSI site, and eliminated GUSB enzymatic activity in expression studies.


Input: Multiple species comparison and the crystal structure of human beta-glucuronidase indicated that E351 is a highly conserved residue most likely essential in maintenance of the enzymes conformation.


Input: BssSI digestion of polymerase chain reaction products amplified from genomic DNA indicated that affected cats were homozygous and cats with half-normal beta-glucuronidase activity were heterozygous for the missense mutation.


Input: Carriers identified in this manner produced affected kittens in prospective breedings, and a feline MPS VII breeding colony has been established..

MPS VII


Input: A common molecular basis for rearrangement disorders on chromosome 22q11.

rearrangement disorders


Input: The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors.

congenital anomaly disorders

malignant tumors


Input: Three congenital anomaly disorders, cat-eye syndrome, der () syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11.

congenital anomaly disorders

cat-eye syndrome

der () syndrome

velo-cardio-facial syndrome

DiGeorge syndrome

VCFS

DGS


Input: VCFS/DGS is the most common syndrome associated with 22q11 rearrangements.

VCFS

DGS


Input: In order to determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS patients were defined by haplotype analysis.

VCFS

DGS


Input: Most VCFS/DGS patients have a similar 3 Mb deletion, some have a nested distal deletion breakpoint resulting in a 1.

VCFS

DGS


Input: 5 Mb deletion and a few rare patients have unique deletions or translocations.


Input: The high prevalence of the disorder in the population and the fact that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements.


Input: To investigate this hypothesis, we developed hamster-human somatic hybrid cell lines from VCFS/DGS patients with all three classes of deletions and we now show that the breakpoints occur within similar low copy repeats, termed LCR22s.

VCFS

DGS


Input: To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients.

VCFS

DGS


Input: We present models to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders.

congenital anomaly disorders


Input: We identified five additional copies of the LCR22 on 22q11 that may mediate other rearrangements leading to disease.


Input: Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies.

myelinopathies


Input: The early growth response 2 gene (EGR2) is a Cys2His2zinc finger transcription factor which is thought to play a role in the regulation of peripheral nervous system myelination.


Input: This idea is based partly on the phenotype of homozygous Krox20 (Egr2) knockout mice, which display hypomyelination of the PNS and a block of Schwann cells at an early stage of differentiation.

hypomyelination of the PNS


Input: Mutations in the human EGR2 gene have recently been associated with the inherited peripheral neuropathies Charcot-Marie-Tooth type 1, Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy.

inherited peripheral neuropathies Charcot-Marie-Tooth type 1

Dejerine-Sottas syndrome

congenital hypomyelinating neuropathy


Input: Three of the four EGR2 mutations are dominant and occur within the zinc finger DNA-binding domain.


Input: The fourth mutation is recessive and affects the inhibitory domain (R1) that binds the NAB transcriptional co-repressors.


Input: A combination of DNA-binding assays and transcriptional analysis was used to determine the functional consequences of these mutations.


Input: The zinc finger mutations affect DNA binding and the amount of residual binding directly correlates with disease severity.


Input: The R1 domain mutation prevents interaction of EGR2 with the NAB co-repressors and thereby increases transcriptional activity.


Input: These data provide insight into the possible disease mechanisms underlying EGR2 mutations and the reason for varying severity and differences in inheritance patterns..


Input: Autosomal recessive familial neurohypophyseal diabetes insipidus with continued secretion of mutant weakly active vasopressin.

Autosomal recessive familial neurohypophyseal diabetes insipidus


Input: Familial neurohypophyseal diabetes insipidus is an autosomal dominant disorder characterized by post-natal development of arginine vasopressin (AVP) deficiency due to mutations in the AVP gene.

Familial neurohypophyseal diabetes insipidus

autosomal dominant disorder

arginine vasopressin (AVP) deficiency


Input: All published mutations affect the signal peptide or the neurophysin-II carrier protein and are presumed to interfere with processing of the preprohormone, leading to neuronal damage.

neuronal damage


Input: We studied an unusual Palestinian family consisting of asymptomatic first cousin parents and three children affected with neurohypophyseal diabetes insipidus, suggesting autosomal recessive inheritance.

neurohypophyseal diabetes insipidus


Input: All three affected children were homozygous and the parents heterozygous for a single novel mutation (C301-> T) in exon 1, replacing Pro7 of mature AVP with Leu (Leu-AVP).


Input: Leu-AVP was a weak agonist with approximately 30-fold reduced binding to the human V2 receptor.


Input: Measured by radioimmunoassay with a synthetic Leu-AVP standard, serum Leu-AVP levels were elevated in all three children and further increased during water deprivation to as high as 30 times normal.


Input: The youngest child (2 years old) was only mildly affected but had Leu-AVP levels similar to her severely affected 8-year-old brother, suggesting that unknown mechanisms may partially compensate for a deficiency of active AVP in very young children..

deficiency of active AVP


Input: X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation.


Input: A somatic mutation in the X linked PIGA gene is responsible for the deficiency of glycosyl phosphatidylinositol (GPI)-anchored proteins on blood cells from patients with paroxysmal nocturnal hemoglobinuria.

deficiency of glycosyl phosphatidylinositol (GPI)-anchored proteins

paroxysmal nocturnal hemoglobinuria


Input: No inherited form of GPI-anchor deficiency has been described.

GPI-anchor deficiency


Input: Because conventional Piga gene knockout is associated with high embryonic lethality in chimeric mice, we used the Cre/loxP system.

embryonic lethality


Input: We generated mice in which two loxP sites flank part of Piga exon 2.


Input: After crossbreeding with female mice of the EIIa-cre strain, the floxed allele undergoes Cre-mediated recombination with high efficiency during early embryonic development.


Input: Because of X chromosome inactivation, female offspring are mosaic for cells that express or lack GPI-linked proteins.


Input: Analysis of mosaic mice showed that in heart, lung, kidney, brain, and liver, mainly wild-type Piga is active, suggesting that these tissues require GPI-linked proteins.


Input: The salient exceptions were spleen, thymus, and red blood cells, which had almost equal numbers of cells expressing the wild-type or the recombined allele, implying that GPI-linked proteins are not essential for the derivation of these tissues.


Input: PIGA (-) cells had no growth advantage, suggesting that other factors are needed for their clonal dominance in patients with paroxysmal nocturnal hemoglobinuria..

paroxysmal nocturnal hemoglobinuria


Input: The C282Y mutation causing hereditary hemochromatosis does not produce a null allele.

hereditary hemochromatosis


Input: Targeted mutagenesis was used to produce two mutations in the murine hemochromatosis gene (Hfe) locus.

hemochromatosis


Input: The first mutation deletes a large portion of the coding sequence, generating a null allele.


Input: The second mutation introduces a missense mutation (C282Y) into the Hfe locus, but otherwise leaves the gene intact.


Input: This mutation is identical to the disease-causing mutation in patients with hereditary hemochromatosis.

hereditary hemochromatosis


Input: Mice carrying each of the two mutations were bred and analyzed.


Input: Homozygosity for either mutation results in postnatal iron loading.


Input: The effects of the null mutation are more severe than the effects of the C282Y mutation.


Input: Mice heterozygous for either mutation accumulate more iron than normal controls.


Input: Interestingly, although liver iron stores are greatly increased, splenic iron is decreased.


Input: We conclude that the C282Y mutation does not result in a null allele..


Input: Genotype-phenotype analysis in X-linked Emery-Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype.

X-linked Emery-Dreifuss muscular dystrophy


Input: Direct sequencing of the emerin gene in 22 families with Emery-Dreifuss muscular dystrophy (EMD) revealed mutations in 21 (95%), confirming that emerin mutations can be identified in the majority of families with X-linked EMD.

Emery-Dreifuss muscular dystrophy

EMD

X-linked EMD


Input: Most emerin mutations result in absence of the protein.


Input: In this study three mutations (a missense mutation Pro183Thr and two in-frame deletions removing residues 95-99 and 236-241, respectively) were unusual in being associated with expression of mutant protein.


Input: The phenotype in these families was compared in detail with the clinical features in cases with typical null mutations.


Input: For the in-frame deletions there were no significant differences.


Input: In the family with the missense mutation the phenotype was milder.


Input: Age at onset was later for first symptoms and for development of ankle contractures and muscle weakness.

ankle contractures

muscle weakness


Input: These findings have diagnostic implications as well as pointing to functionally important regions of the emerin protein..


Input: Severe clinical expression in X-linked Emery-Dreifuss muscular dystrophy.

X-linked Emery-Dreifuss muscular dystrophy


Input: X-linked Emery-Dreifuss muscular dystrophy (EDMD) is a relatively rare benign neuromuscular disorder which can vary remarkably in onset, course and severity.

X-linked Emery-Dreifuss muscular dystrophy

EDMD

benign neuromuscular disorder


Input: In the present study, a TCTAC deletion spanning the nucleotides 631-635 of the emerin gene caused an unusually severe disease phenotype including loss of ambulation and severe muscle wasting in two affected brothers.

loss of ambulation

muscle wasting


Input: The same mutation has been reported previously in an unrelated family showing a significantly milder phenotype.


Input: The interfamilial heterogeneity in distribution and in severity of the features in the two families point to environmental or genetic modification as the cause of clinical variability in Emery-Dreifuss muscular dystrophy..

Emery-Dreifuss muscular dystrophy


Input: Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men.

prostate cancer


Input: BACKGROUND Families with a high incidence of hereditary breast cancer, and subsequently shown to have terminating mutations in BRCA1 or BRCA2, appear to have a higher incidence of prostate cancer among male relatives.

hereditary breast cancer

prostate cancer


Input: We aimed to determine whether the common germline mutations of BRCA1 or BRCA2 in Ashkenazi Jewish men predisposed them to prostate cancer.

prostate cancer


Input: METHODS We examined genomic DNA from 83 (for BRCA1 185delAG) or 82 (for BRCA2 6174delT) Ashkenazi Jewish prostate cancer patients, most of whom were treated at a relatively young age, for the most common germline mutation in each gene seen in the Ashkenazi population.

prostate cancer


Input: RESULTS Our study should have been able to detect a 4-5-fold increase in the risk of prostate cancer due to mutation of BRCA1 or BRCA2.

prostate cancer


Input: However, only one (1. 15%; 95% confidence interval, 0-3. 6%) of the patients was heterozygous for the BRCA1 mutant allele, and only two were heterozygous for the BRCA2 mutation (2. 4%; 95% confidence interval, 0-6. 2%).


Input: CONCLUSIONS The incidence of each of the germline mutations in these prostate cancer patients closely matched their incidence (about 1%) in the general Ashkenazi Jewish population.

prostate cancer


Input: This suggests that unlike cases of breast and ovarian cancers, mutations in BRCA1 or BRCA2 do not significantly predispose men to prostate cancer

breast and ovarian cancers


Input: Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma.

hepatoblastoma


Input: Hepatoblastoma is a rare malignant tumor of the liver that occurs in children at an average age of 2 to 3 years.

Hepatoblastoma

malignant tumor of the liver


Input: Epidemiologic studies have shown an increased frequency of this tumor type in families affected by adenomatous polyposis coli.

tumor

adenomatous polyposis coli


Input: In addition to the epidemiologic data, molecular genetic studies suggest that inactivation of the APC tumor suppressor may be involved in hepatoblastoma tumorigenesis.

APC tumor

hepatoblastoma


Input: A major function of APC is the downregulation of beta-catenin, a transcription-activating protein with oncogenic potential.


Input: In an ongoing immunohistochemical study of beta-catenin expression in sporadic cases of tumor types that are associated with adenomatous polyposis coli, we observed increased beta-catenin levels in the cytoplasm and in the nuclei of three investigated hepatoblastomas.

tumor

adenomatous polyposis coli

hepatoblastomas


Input: Sequencing of exon 3 of the beta-catenin gene (CTNNB1) revealed an activating mutation in one of the tumor samples.

tumor


Input: Our data indicate for the first time that beta-catenin accumulation may play a role in the development of hepatoblastoma and that activating mutations of the beta-catenin gene may substitute biallelic APC inactivation in this tumor type.

hepatoblastoma

tumor


Input: Genes Chromosomes Cancer 25 399-402, 1999..


Input: Decrease in GTP cyclohydrolase I gene expression caused by inactivation of one allele in hereditary progressive dystonia with marked diurnal fluctuation.

hereditary progressive dystonia


Input: Hereditary progressive dystonia with marked diurnal fluctuation (HPD; dopa-responsive dystonia, DRD) have been recently found to be caused by a genetic defect in the GTP cyclohydrolase I (GCH1) gene.

Hereditary progressive dystonia

HPD

dopa-responsive dystonia

DRD

genetic defect


Input: In this study, we quantified the mRNA level of GCH1 in phytohemagglutinin (PHA)-stimulated mononuclear blood cells from one Japanese family that do not have a mutation in the coding region or splice junctions of the gene.


Input: The results showed that the amounts of the GCH1 mRNA were decreased to about 40% of the normal level in both patients and carriers.


Input: In addition, we found that the GCH1 mRNA was transcribed from only one allele, indicating that the other allele was in an inactive state.


Input: These results suggest that some novel mutations should exist on one of the alleles in some unknown region of the GCH1 gene, and may decrease the GCH1 mRNA causing the HPD/DRD symptoms..

HPD

DRD


Input: Sulfate transport is not impaired in pendred syndrome thyrocytes.

pendred syndrome


Input: Pendred syndrome is the most common form of syndromic deafness, characterized by dyshormonogenic goiter associated with sensory-neural deafness.

Pendred syndrome

syndromic deafness

dyshormonogenic goiter

sensory-neural deafness


Input: The gene responsible for the disease (PDS) has been cloned, but its function is as yet unknown and the connection between thyroid goiter and sensory-neural deafness remains an enigma.

PDS

thyroid goiter

sensory-neural deafness


Input: PDS codes for a novel protein, pendrin, which is closely related to a number of sufate transporters.


Input: Mechanisms by which abnormal sulfate transport could deleteriously affect iodide organification have been proposed.


Input: We tested sulfate transport in thyrocytes obtained from Pendred syndrome patients and found that it was not defective.

Pendred syndrome


Input: This suggests that pendrin in fact may not be a sulfate transporter, and emphasizes the importance of functional studies on this novel protein..


Input: Small deletions in the type II collagen triple helix produce kniest dysplasia.

kniest dysplasia


Input: Kniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss.

Kniest dysplasia

type II collagenopathy

kyphoscoliosis

midface hypoplasia

myopia

hearing loss


Input: Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia.

Kniest dysplasia


Input: All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations.


Input: Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene.


Input: We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia.

Kniest dysplasia


Input: Sequencing of the index patients genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20.

Kniest dysplasia


Input: A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case.


Input: The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele.


Input: These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype..

Kniest dysplasia

Kniest dysplasia


Input: Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene.

Classical galactosemia


Input: Classical galactosemia is caused by a deficiency in activity of the enzyme galactose-1-phosphate uridyl transferase (GALT), which, in turn, is caused by mutations at the GALT gene.

Classical galactosemia


Input: The disorder exhibits considerable allelic heterogeneity and, at the end of 1998, more than 150 different base changes were recorded in 24 different populations and ethnic groups in 15 countries worldwide.


Input: The mutations most frequently cited are Q188R, K285N, S135L, and N314D.


Input: Q188R is the most common mutation in European populations or in those predominantly of European descent.


Input: Overall, it accounts for 60-70% of mutant chromosomes, but there are significant differences in its relative frequency in individual populations.


Input: Individuals homoallelic for Q188R tend to have a severe phenotype and this is in keeping with the virtually complete loss of enzyme activity observed in in vitro expression systems.


Input: Globally, K285N is rarer, but in many European populations it can be found on 25-40% of mutant chromosomes.


Input: It is invariably associated with a severe phenotype.


Input: S135L is found almost exclusively in African Americans.


Input: In vitro expression results are discrepant, but some individuals carrying S135L appear to exhibit GALT activity in some tissues.


Input: Duarte 1 (or Los Angeles) and Duarte 2 (or Duarte) variants carry the same amino acid substitution, N314D, even though D1 is associated with increased erythrocyte GALT activity and D2 with reduced activity.


Input: N314D is in linkage disequilibrium with other base changes that differ on the D1 and D2 alleles.


Input: N314D does not impair GALT activity in in vitro expression systems.


Input: However, there are differences in the abundance of GALT protein in lymphoblastoid cells lines from D2 and D1 individuals.


Input: It is unclear whether the specific molecular changes that distinguish the D1 and D2 alleles account for the different activities.


Input: The considerable genetic heterogeneity documented to date undoubtedly contributes to the phenotypic heterogeneity that is observed in galactosemia.

galactosemia


Input: The additional effects of nonallelic variation and other constitutional factors on phenotypic variability remain to be elucidated..


Input: Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC.

VHL

sporadic renal cell carcinoma

VHL

RCC


Input: To investigate the nature of somatic von Hippel-Lindau (VHL) mutations, we analyzed 173 primary sporadic human renal cell carcinomas for mutations of the VHL tumor suppressor gene, using polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis (SSCP) of DNA.

von Hippel-Lindau

VHL

renal cell carcinomas

VHL tumor


Input: We detected abnormal SSCP pattern in 73 samples.


Input: After sequencing, we identified microdeletions in 58% of cases, microinsertions in 17%, nonsense mutations in 8%, and missense mutations in 17%.


Input: Among these mutations, 50% correspond to new mutations.


Input: VHL mutations were found only in the nonpapillary renal cell carcinoma (RCC) subtype, as previously reported.

VHL

nonpapillary renal cell carcinoma

RCC


Input: To compare somatic and germline mutations, we used the VHL database, which includes 507 mutations.

VHL


Input: The study of mutational events revealed a significant difference between somatic and germline mutations with mutations leading to truncated proteins observed in 78% of somatic mutations vs only 37% in germline mutations (P < 0. 001).


Input: We postulated that a specific pattern of VHL mutations is associated with sporadic RCC.

VHL

sporadic RCC


Input: This pattern corresponds to mutations leading mainly to truncated proteins with few specific missense mutations.


Input: We then analyzed the occurrence of RCC in VHL families, based on the nature of mutations.

RCC

VHL


Input: We observed RCC in at least one member of the VHL families in 77% of cases with mutations leading to truncated proteins versus 55% in cases with missense mutations (P < 0. 05).

RCC

VHL


Input: Thus, mutations resulting in truncated proteins may lead to a higher risk of RCC in VHL patients

RCC

VHL


Input: Defective CTLA-4 cycling pathway in Chediak-Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation.

Chediak-Higashi syndrome


Input: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, also known as CD152) has been shown to play a major role in the regulation of T cell activation.


Input: Its membrane expression is highly regulated by endocytosis and trafficking through the secretory lysosome pathway.


Input: Chediak-Higashi syndrome (CHS) is an inherited disorder caused by mutations in the lysosomal trafficking regulator gene, LYST.

Chediak-Higashi syndrome

CHS

inherited disorder


Input: It results in defective membrane targeting of the proteins present in secretory lysosomes, and it is associated with a variety of features, including a lymphoproliferative syndrome with hemophagocytosis.

lymphoproliferative syndrome

hemophagocytosis


Input: The murine equivalent of CHS, beige mice, present similar characteristics but do not develop the lymphoproliferative syndrome.

CHS

lymphoproliferative syndrome