Characterisation of the unstable expanded CAG repeat in the MJD1 gene in four Brazilian families of Portuguese descent with Machado-Joseph disease

• Published in: Journal of medical genetics Vol. 32; no. 10; pp. 827 - 830
• Main Authors: Stevanin, Giovanni, Cassa, Eloy, Cancel, Géraldine, Abbas, Nacer, Dürr, Alexandra, Jardim, Edymar, Agid, Yves, Sousa, Patricia S, Brice, Alexis
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.10.1995; BMJ; BMJ Publishing Group LTD
• Subjects: Adult; Aged; Ataxin; Ataxin-3; Biological and medical sciences; Brazil; Brief Papers; Chromosome 14; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Hereditary diseases; Humans; Linkage Disequilibrium; Machado-Joseph disease; Machado-Joseph Disease - genetics; Male; Medical sciences; Middle Aged; Molecular modelling; Mutation; Nerve Tissue Proteins; Neurodegenerative diseases; Neurology; Nuclear Proteins; Polyglutamine; Portugal; Proteins - genetics; Repressor Proteins; Trinucleotide repeat diseases; Trinucleotide Repeats; Human; Nervous system diseases; Joseph disease; Family study; Repeated sequence; Trinucleotide; Metabolic diseases; Enzymopathy; Genetic disease; Central nervous system disease; Genetics; Instability; Degenerative disease; Mutation; Expansion
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.32.10.827

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder which has been shown to result, in Japanese families, from the expansion of a CAG repeat in the MJD1 gene on chromosome 14q. We show that the same molecular mechanism is responsible for MJD in four large Brazilian kindreds of Portuguese descent. The behaviour of the mutation was evaluated in 28 affected and 19 asymptomatic gene carriers. The number of repeats in the expanded alleles ranged from 66 to 77 with a strong negative correlation with age at onset (r=0·79). A mean 1·6 repeats increase from generation to generation correlated with clinical anticipation. Instability of the CAG repeat was bidirectional, with expansions as well as contractions, and was more marked in paternal transmissions. Finally, linkage disequilibrium was complete at locus D14S280 in the four Portuguese-Brazilian kindreds and four previously reported French families with the same mutation, which suggests the existence of a common founder.