Dataset Information

Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations.

ABSTRACT: Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder, results from the deficient activity of acid beta-glucosidase (GBA). Type 1 disease is panethnic but is more prevalent in individuals of Ashkenazi Jewish (AJ) descent. Of the causative GBA mutations, N370S is particularly frequent in the AJ population, (q approximately .03), whereas the 84GG insertion (q approximately .003) occurs exclusively in the Ashkenazim. To investigate the genetic history of these mutations in the AJ population, short tandem repeat (STR) markers were used to map a 9.3-cM region containing the GBA locus and to genotype 261 AJ N370S chromosomes, 60 European non-Jewish N370S chromosomes, and 62 AJ 84GG chromosomes. A highly conserved haplotype at four markers flanking GBA (PKLR, D1S1595, D1S2721, and D1S2777) was observed on both the AJ chromosomes and the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common to both populations. Of note, the presence of different divergent haplotypes suggested the occurrence of de novo, recurrent N370S mutations. In contrast, a different conserved haplotype at these markers was identified on the 84GG chromosomes, which was unique to the AJ population. On the basis of the linkage disequilibrium (LD) delta values, the non-Jewish European N370S chromosomes had greater haplotype diversity and less LD at the markers flanking the conserved haplotype than did the AJ N370S chromosomes. This finding is consistent with the presence of the N370S mutation in the non-Jewish European population prior to the founding of the AJ population. Coalescence analyses for the N370S and 84GG mutations estimated similar coalescence times, of 48 and 55.5 generations ago, respectively. The results of these studies are consistent with a significant bottleneck occurring in the AJ population during the first millennium, when the population became established in Europe.

SUBMITTER: Diaz GA

PROVIDER: S-EPMC1378046 | biostudies-other | 2000 Jun

REPOSITORIES: biostudies-other

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Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations.

Diaz G A GA Gelb B D BD Risch N N Nygaard T G TG Frisch A A Cohen I J IJ Miranda C S CS Amaral O O Maire I I Poenaru L L Caillaud C C Weizberg M M Mistry P P Desnick R J RJ

American journal of human genetics 20000421 6

Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder, results from the deficient activity of acid beta-glucosidase (GBA). Type 1 disease is panethnic but is more prevalent in individuals of Ashkenazi Jewish (AJ) descent. Of the causative GBA mutations, N370S is particularly frequent in the AJ population, (q approximately .03), whereas the 84GG insertion (q approximately .003) occurs exclusively in the Ashkenazim. To investigate the genetic history of these mutations in the ...[more]

PMID: 10777718

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Project description:Information on age-specific risk for Parkinson disease (PD) in patients with Gaucher disease (GD) and glucocerebrosidase (GBA) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations.To estimate the age-specific risk for PD in Ashkenazi Jewish patients with type 1 GD and in GBA heterozygotes.The study included patients with GD from 2 tertiary centers, Shaare Zedek Medical Center, Jerusalem, Israel (n?=?332) and Mount Sinai School of Medicine, New York, New York (n?=?95). GBA noncarrier non-PD spouse control participants were recruited at the Center for Parkinson's Disease at Columbia University, New York (n?=?77). All participants were Ashekanzi Jewish and most patients (98.1%) with GD carried at least 1 N370S mutation.The main outcome measure was a diagnosis of PD. Diagnosis was established in patients with GD on examination. We used a validated family history interview that identifies PD with a sensitivity of 95.5% and specificity of 96.2% to identify PD in family members. Kaplan-Meier survival curves were used to estimate age-specific PD risk among patients with GD (n?=?427), among their parents who are obligate GBA mutation carriers (heterozygotes, n?=?694), and among noncarriers (parents of non-PD, non-GD control participants, n?=?154). The age-specific risk was compared among groups using the log-rank test.Among those who developed PD, patients with GD had a younger age at onset than GBA heterozygotes (mean, 54.2 vs 65.2 years, respectively; P?=?.003). Estimated age-specific risk for PD at 60 and 80 years of age was 4.7% and 9.1% among patients with GD, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among noncarriers, respectively. The risk for PD was higher in patients with GD than noncarriers (P?=?.008, log-rank test) and in heterozygotes than noncarriers (P?=?.03, log-rank test), but it did not reach statistical significance between patients with GD and GBA heterozygotes (P?=?.07, log-rank test).Patients with GD and GBA heterozygotes have an increased age-specific risk for PD compared with control individuals, with a similar magnitude of PD risk by 80 years of age; however, the number of mutant alleles may play an important role in age at PD onset.

Project description:Crohn disease (CD), an inflammatory bowel disease, is a multifactorial trait with the highest frequency in Ashkenazi Jewish (AJ) individuals of Central European origin. Recently, three common predisposing CARD15 mutations (R702W, G908R, and 1007fs) and a polymorphism (P268S) were identified. To determine whether CARD15 mutations account for the higher prevalence of CD in AJ individuals, the haplotypes and allele frequencies of the common mutations and variants were assessed in 219 members of 50 AJ and 53 members of 10 Sephardi/Oriental Jewish (SOJ) multiplex families with CD, in 36 AJ patients with sporadic CD, and in 246 AJ and 82 SOJ controls. A higher frequency of CARD15 mutations was found in AJ patients from multiplex families with CD from Central (44.0%) versus Eastern (24.0%) Europe, especially for G908R and 1007fs, and in SOJ patients (34.5%) compared with AJ (10.1%) or SOJ (5.4%) controls. Contrary to expectation, the frequency of the common mutations was slightly lower in AJ patients with CD (30.1%) than in SOJ patients with CD (34.5%). The 702W allele was associated with both the P268 and 268S alleles. CARD15 mutation frequencies were greater in affected sib pairs than in sporadic CD cases but actually decreased in families with three or more affected sibs, raising the possibility of genetic heterogeneity. Similarly, our linkage evidence on chromosome 16 was diminished in the families with three or more affected sibs compared with sib pairs. Screening the CARD15 gene for rare variants revealed five novel changes (D113N, D357A, I363F, L550V, and N852S) of which N852S occurred only in AJ individuals and may be disease predisposing. Also, there was no evidence for increased risk associated with the recently described IVS(+158) single-nucleotide polymorphism. Although the AJ controls appear to have a higher frequency of CARD15 mutations than the SOJ controls, it is unlikely that this difference fully explains the excess frequency of CD in the AJ population.

Dataset Information

Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations.

Publications

Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations.

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