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Yemenite-Jewish families with Machado-Joseph disease (MJD/SCA3) share a recent common ancestor.

ABSTRACT: In 1994, a kindred from Yemen was described as the first Jewish family with Machado-Joseph disease (MJD/SCA3), a dominant ataxia caused by the expansion of a (CAG)_n above 61 repeats, in ATXN3. MJD is spread worldwide due to an ancient variant of Asian origin (the Joseph lineage). A second, more recent, independent expansion arose in a distinct haplotype (Machado lineage); other possible origins are still under study. We haplotyped 46 MJD patients and relatives, from 6 Israeli Yemenite families, and 100 normal chromosomes from that population, for 30 SNPs spreading 15?kb around the (CAG)_n, and 8 STRs and 1 indel in the flanking regions. All six families shared an extended haplotype, showing no variants or recombination after a common origin, but differing in two SNPs (rs12895357 and rs12588287) from the Joseph lineage. To test for a new mutational origin in this population, we searched for the presence of that haplotype in Yemenite-Jewish controls. Only one (1%) normal (CAG)₃₂ allele showed an extended STR-haplotype genetically closer to MJD than normal haplotypes (genetic distance, D_A, 0.43 versus 0.53). That normal allele could be explained either by (1) the introduction of both normal and expanded alleles carrying this "Joseph-like" haplotype into the genetic pool of the Yemenite population; or by (2) a large contraction from the expanded CAG range. Based on the lack of STR diversity in MJD Yemenite-Jewish families, and on high frequency of this Joseph-like haplotype among African controls (23.2%), expanded alleles seem to have been introduced very recently (<400 years ago) from Africa.

SUBMITTER: Sharony R

PROVIDER: S-EPMC6871535 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Yemenite-Jewish families with Machado-Joseph disease (MJD/SCA3) share a recent common ancestor.

Sharony Reuven R Martins Sandra S Costa Inês P D IPD Zaltzman Roy R Amorim António A Sequeiros Jorge J Gordon Carlos R CR

European journal of human genetics : EJHG 20190612 11

In 1994, a kindred from Yemen was described as the first Jewish family with Machado-Joseph disease (MJD/SCA3), a dominant ataxia caused by the expansion of a (CAG)<sub>n</sub> above 61 repeats, in ATXN3. MJD is spread worldwide due to an ancient variant of Asian origin (the Joseph lineage). A second, more recent, independent expansion arose in a distinct haplotype (Machado lineage); other possible origins are still under study. We haplotyped 46 MJD patients and relatives, from 6 Israeli Yemenite ...[more]

PMID: 31189928

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Project description:Machado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), represents the most common form of SCA worldwide. MJD is an autosomal dominant neurodegenerative disorder of late onset, involving predominantly the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems; although sharing features with other SCAs, the identification of minor, but more specific signs, facilitates its differential diagnosis. MJD presents strong phenotypic heterogeneity, which has justified the classification of patients into three main clinical types. Main pathological lesions are observed in the spinocerebellar system, as well as in the cerebellar dentate nucleus. MJD's causative mutation consists in an expansion of an unstable CAG tract in exon 10 of the ATXN3 gene, located at 14q32.1. Haplotype-based studies have suggested that two main founder mutations may explain the present global distribution of the disease; the ancestral haplotype is of Asian origin, and has an estimated age of around 5,800 years, while the second mutational event has occurred about 1,400 years ago. The ATXN3 gene encodes for ataxin-3, which is ubiquitously expressed in neuronal and non-neuronal tissues, and, among other functions, is thought to participate in cellular protein quality control pathways. Mutated ATXN3 alleles consensually present about 61 to 87 CAG repeats, resulting in an expanded polyglutamine tract in ataxin-3. This altered protein gains a neurotoxic function, through yet unclear mechanisms. Clinical variability of MJD is only partially explained by the size of the CAG tract, which leaves a residual variance that should be explained by still unknown additional factors. Several genetic tests are available for MJD, and Genetic Counseling Programs have been created to better assist the affected families, namely on what concerns the possibility of pre-symptomatic testing. The main goal of this review was to bring together updated knowledge on MJD, covering several aspects from its initial descriptions and clinical presentation, through the discovery of the causative mutation, its origin and dispersion, as well as molecular genetics aspects considered essential for a better understanding of its neuropathology. Issues related with molecular testing and Genetic Counseling, as well as recent progresses and perspectives on genetic therapy, are also addressed.

Dataset Information

Yemenite-Jewish families with Machado-Joseph disease (MJD/SCA3) share a recent common ancestor.

Publications

Yemenite-Jewish families with Machado-Joseph disease (MJD/SCA3) share a recent common ancestor.

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