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

Article metrics


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2


  1. 1.

    Wang J, Shen L, Lei L, Xu Q, Zhou J, Liu Y, et al. Spinocerebellar ataxias in mainland China: an updated genetic analysis among a large cohort of familial and sporadic cases. J Cent South Univ Med Sci. 2011;36:482–9.

  2. 2.

    de Castilhos RM, Furtado GV, Gheno TC, Schaeffer P, Russo A, Barsottini O, et al. Spinocerebellar ataxias in Brazil--frequencies and modulating effects of related genes. Cerebellum. 2014;13:17–28.

  3. 3.

    Vale J, Bugalho P, Silveira I, Sequeiros J, Guimaraes J, Coutinho P. Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal. Eur J Neurol. 2010;17:124–8.

  4. 4.

    Boonkongchuen P, Pongpakdee S, Jindahra P, Papsing C, Peerapatmongkol P, Wetchaphanphesat S, et al. Clinical analysis of adult-onset spinocerebellar ataxias in Thailand. BMC Neurol. 2014;14:75.

  5. 5.

    Schols L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol. 1997;42:924–32.

  6. 6.

    Zhao Y, Tan EK, Law HY, Yoon CS, Wong MC, Ng I. Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore. Clin Genet. 2002;62:478–81.

  7. 7.

    Martins S, Sequeiros J. Origins and spread of Machado–Joseph disease ancestral mutational events. In: Almeida LP, Nóbrega C, editors. Adv Exp Med Biol. 2018;1049:243–54.

  8. 8.

    Goldberg-Stern H, D’Jaldetti R, Melamed E, Gadoth N. Machado–Joseph (Azorean) disease in a Yemenite Jewish family in Israel. Neurology. 1994;44:1298–301.

  9. 9.

    Lerer I, Merims D, Abeliovich D, Zlotogora J, Gadoth N. Machado–Joseph disease: correlation between the clinical features, the CAG repeat length and homozygosity for the mutation. Eur J Hum Genet. 1996;4:3–7.

  10. 10.

    Zaltzman R, Sharony R, Klein C, Gordon CR. Spinocerebellar ataxia type 3 in Israel: phenotype and genotype of a Jew Yemenite subpopulation. J Neurol. 2016;263:2207–14.

  11. 11.

    Coutinho P, Andrade C. Autosomal dominant system degeneration in Portuguese families of the Azores Islands. A new genetic disorder involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions. Neurology. 1978;28:703–9.

  12. 12.

    Subramony SH, Hernandez D, Adam A, Smith-Jefferson S, Hussey J, Gwinn-Hardy K, et al. Ethnic differences in the expression of neurodegenerative disease: Machado–Joseph disease in Africans and Caucasians. Mov disord. 2002;17:1068–71.

  13. 13.

    Gwinn-Hardy K, Singleton A, O’Suilleabhain P, Boss M, Nicholl D, Adam A, et al. Spinocerebellar ataxia type 3 phenotypically resembling parkinson disease in a black family. JAMA Neurol. 2001;58:296–9.

  14. 14.

    Coutinho P. Doença de Machado-Joseph: Tentativa de definição. University of Porto, Portugal; 1992.

  15. 15.

    Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994;8:221–8.

  16. 16.

    Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, et al. Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am J Hum Genet. 1995;57:54–61.

  17. 17.

    Maciel P, Costa MC, Ferro A, Rousseau M, Santos CS, Gaspar C, et al. Improvement in the molecular diagnosis of Machado-Joseph disease. JAMA Neurol. 2001;58:1821–7.

  18. 18.

    Maruyama H, Nakamura S, Matsuyama Z, Sakai T, Doyu M, Sobue G, et al. Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease. Hum Mol Genet. 1995;4:807–12.

  19. 19.

    Martins S, Calafell F, Gaspar C, Wong VC, Silveira I, Nicholson GA, et al. Asian origin for the worldwide-spread mutational event in Machado-Joseph disease. JAMA Neurol. 2007;64:1502–8.

  20. 20.

    Martins S, Soong BW, Wong VC, Giunti P, Stevanin G, Ranum LP, et al. Mutational origin of Machado–Joseph disease in the Australian Aboriginal communities of Groote Eylandt and Yirrkala. JAMA Neurol. 2012;69:746–51.

  21. 21.

    Costa IPD, Almeida BC, Sequeiros J, Amorim A, Martins S. A pipeline to assess disease-associated haplotypes in repeat expansion disorders: the example of MJD/SCA3 locus. Front Genet. 2019;10:38.

  22. 22.

    Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68:978–89.

  23. 23.

    Bandelt HJ, Forster P, Rohl A. Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol. 1999;16:37–48.

  24. 24.

    Takezaki N, Nei M, Tamura K. POPTREE2: software for constructing population trees from allele frequency data and computing other population statistics with windows interface. Mol Biol Evol. 2010;27:747–52.

  25. 25.

    Excoffier L, Lischer HE. Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour. 2010;10:564–7.

  26. 26.

    Gaspar C, Lopes-Cendes I, Hayes S, Goto J, Arvidsson K, Dias A, et al. Ancestral origins of the Machado–Joseph disease mutation: a worldwide haplotype study. Am J Hum Genet. 2001;68:523–8.

Download references


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.

Author information

Correspondence to Sandra Martins or Jorge Sequeiros.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark