Ancestral Origins of the Machado-Joseph Disease Mutation: A Worldwide Haplotype Study

• Published in: American journal of human genetics Vol. 68; no. 2; pp. 523 - 528
• Main Authors: Gaspar, C., Lopes-Cendes, I., Hayes, S., Goto, J., Arvidsson, K., Dias, A., Silveira, I., Maciel, P., Coutinho, P., Lima, M., Zhou, Y.-X., Soong, B.-W., Watanabe, M., Giunti, P., Stevanin, G., Riess, O., Sasaki, H., Hsieh, M., Nicholson, G.A., Brunt, E., Higgins, J.J., Lauritzen, M., Tranebjaerg, L., Volpini, V., Wood, N., Ranum, L., Tsuji, S., Brice, A., Sequeiros, J., Rouleau, G.A.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.02.2001; University of Chicago Press; The American Society of Human Genetics
• Subjects: Alleles; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA - genetics; Family Health; Founder Effect; Gene Frequency; Genetics, Population; Genotype; Haplotypes; Humans; Linkage Disequilibrium; Machado-Joseph Disease - genetics; Medical sciences; Microsatellite Repeats; MJD1 gene; Molecular Sequence Data; Mutation; Neurology; Polymorphism, Single Nucleotide; World; Portugal; Human; Nervous system diseases; Joseph disease; Family study; Pathogenesis; Metabolic diseases; Founder effect; Enzymopathy; Genetic determinism; Cerebral disorder; Microsatellite DNA; Central nervous system disease; Degenerative disease; Haplotype; Aminoacid disorder; Polymorphism
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/318184

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single–base-pair polymorphisms ( A 669TG/ G 669TG, C 987GG/ G 987GG, and TA A 1118/TA C 1118). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD.