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, DA, 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.
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The authors thank the Israeli Machado-Joseph Association and all patients and families for their participation in this study.
This work was financed by the FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020; by the project NORTE-01-0145-FEDER-000008, supported by the Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund; and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Inovação, in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01–0145-FEDER-007274). SM is funded by the FCT research contract IF/00930/2013.
Conflict of interest
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