Mutations of the Hexosaminidase A Gene in Ashkenazi and Non-Ashkenazi Jews

Peleg, Leah; Karpati, Mazal; Gazit, Ephraim; Raas‐Rothschild, Annick; Goldman, Boleslaw

doi:10.1006/bmmb.1994.1029

Cited by 12 publications

(14 citation statements)

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“…Frisch et al (2004) identified a conserved c.1278insTATC haplotype in 55 unrelated AJ individuals, suggesting the occurrence of a common founder in Central Europe. The c.1278insTATC mutation was diagnosed in 73.2% of Australian carriers (Sydney, 69.8%; Melbourne, 81.0%), comparable to the figure of 70-82% reported in other AJ populations (Peleg et al 1994;Grebner and Tomczak 1991;Paw et al 1990;Myerowitz and Costigan 1988). However, grandparents' birthplace in specific European countries or regions showed no significant relationship with grandchildren's risk of c.1278insTATC carrier status (Table 7).…”

Section: Discussionsupporting

confidence: 69%

“…Responses were stratified into regions (Table 2), based on political geographic boundaries and language to reflect Jewish community life in Europe prior to World War II (WWII), with additional reference to the Australian Bureau of Statistics Standard Australian Classification of Countries (second edition) (Harper 2008). The resultant geographic groupings we used were comparable to those used in past published papers investigating the frequencies of TSD carriers amongst AJ and non-AJ groups during the premolecular and molecular era (Risch et al 2003;Peleg et al 1994;Myrianthopoulos and Melnick 1977).…”

Section: Methodsmentioning

confidence: 98%

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Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421 + 1G > C mutation in individuals with South African heritage

2011

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Section: Discussionsupporting

confidence: 69%

Section: Methodsmentioning

confidence: 98%

Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421 + 1G > C mutation in individuals with South African heritage

2011

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“…More information concerning the natural history of TSD can be extracted by comparing frequencies in nonAshkenazi Jews (non-AJs) with those in AJs. Peleg et al (1994) have reported the relative frequencies of the major HEXA mutations in Hex-A-deficient non-AJs living in Israel. Based on these frequencies and assuming a total allele frequency of 0.002 (Gravel et al 2001), Risch (2001) has estimated the absolute frequency of each mutation.…”

Section: Introductionmentioning

confidence: 99%

Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis

et al. 2004

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The 1278insTATC is the most prevalent beta-hexosaminidase A ( HEXA) gene mutation causing Tay-Sachs disease (TSD), one of the four lysosomal storage diseases (LSDs) occurring at elevated frequencies among Ashkenazi Jews (AJs). To investigate the genetic history of this mutation in the AJ population, a conserved haplotype (D15S981:175-D15S131:240-D15S1050:284-D15S197:144-D15S188:418) was identified in 1278insTATC chromosomes from 55 unrelated AJ individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the insertion was found to be 40+/-12 generations (95% confidence interval: 30-50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th-9th century. This corresponds with the demographic expansion of AJs in central Europe, following the founding of the Ashkenaz settlement in the early Middle Ages. The results are consistent with the geographic distribution of the main TSD mutation, 1278insTATC being more common in central Europe, and with the coalescent times of mutations causing two other LSDs, Gaucher disease and mucolipidosis type IV. Evidence for the absence of a determinant positive selection (heterozygote advantage) over the mutation is provided by a comparison between the estimated age of 1278insTATC and the probability of the current AJ frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust parsimonious hypothesis explaining the spread of 1278insTATC-linked TSD in AJ individuals.

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“…This genetic homogeneity is paralleled by a relatively homogeneous socioeconomic and educational status. Inbreeding in this population has allowed successful genetic research in Ashkenazi Jews, including the characterization of multiple rare autosomal recessive disorders such as Tay-Sachs disease [48], factor XI deficiency [49], and hyperinsulinemic hypoglycemia of infancy (i.e., sulfonylurea receptor mutations) [50], as well as common diseases such as breast and ovarian cancer (i.e., BRCA1 and BRCA2 gene mutations) [8]. A limitation of this model is the lack of inclusion of a complex geneenvironment interaction.…”

Section: Methodsmentioning

confidence: 99%

Buffering Mechanisms in Aging: A systems approach towards uncovering the genetic component of aging

Bergman

Atzmon

et al. 2005

PLoS Comput Biol

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An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the ''oldest old'' Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows diseaserelated genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using more than 1,200 subjects between the sixth and eleventh decades of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidatebuffering mechanism and its candidate age-related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying subnetwork of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar; thus, the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.

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Mutations of the Hexosaminidase A Gene in Ashkenazi and Non-Ashkenazi Jews

Cited by 12 publications

References 0 publications

Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421 + 1G > C mutation in individuals with South African heritage

Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421 + 1G > C mutation in individuals with South African heritage

Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis

Buffering Mechanisms in Aging: A systems approach towards uncovering the genetic component of aging

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