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Molecular characteristics of Machado-Joseph disease mutation in 25 newly described Brazilian families
Iscia Lopes-CendesI,*; Hélio G.A. TeiveII; Francisco CardosoIII; Erika M. VianaIII; Maria E. CalcagnottoIV; Jaderson C. da CostaIV; Paulo C. Trevisol-BittencourtV; Jayme A. Maciel VI; Marylene RousseauI; André S. SantosVII; Abelardo Q.C. AraújoVIII; G.A. RouleauI
ICentre for Research in Neuroscience and the Montreal General Hospital Research Institute, McGill University, Montreal, Quebec, Canada. E-mail: iscia@turing.unicamp.br. Send correspondence to I.L.-C. *Present address: Departamento de Genética Médica, Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (UNICAMP), Cidade Universitária Zeferino Voz, Caixa Postal 6111, Distrito de Barão Geraldo, 13083-970 Campinas, SP, Brasil. Tel. (019) 788-8210, Fax (019) 239-3114.
IIServiço de Neurologia, Universidade Federal do Paraná, Curitiba, PR, Brasil.
IIIDepartamento de Neurologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
IVDepartamento de Neurologia, Hospital Universitário São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brasil.
VServiço de Neurologia, Hospital Universitário da Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil.
VIDepartamento de Neurologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.
VIIHospital de Caridade, Florianópolis, SC, Brasil.
VIIIDepartamento de Neurologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
ABSTRACT
Machado-Joseph disease (MJD) is a form of autosomal dominant spinocerebellar ataxia first described in North-American patients originating from the Portuguese islands of the Azores. Clinically this disorder is characterized bylate onset progressive ataxia w,ith associated features, such as: ophthalmoplegia, pyramidal and extrapyramidal signs and distal muscular atrophies. The causative mutation is an expansion of a CAG repeat in the coding region of the MIDI gene.
We have identified 25 unrelated families segregating the MID mutation during a large collaborative study of spinocerebellar ataxias in Brazil. In the present study a total of 62 family members were genotyped for the CAG repeat in the MIDI gene, as well as 63 non-MJD individuals (126 normal chromosomes), used as normal controls. We observed a wide gap between the size range of the normal and expanded CAG repeats: the normal allele had from 12 to 33 CAGs (mean =23 CAGs), whereas the expanded alleles ranged from 66 to 78 CAGs (mean =71.5 CAGs). There were no differences in CAG tract length according to gender of affected individuals or transmitting parent. We observed a significant negative correlation between age at onset of the disease and length of the CAG tract in the expended allele (r =-0.6, P =0.00006); however, the size of the expanded CAG repeat could explain only about 40% of the variability in age at onset (r2 =0.4).
Keywords: Machado-Joseph disease.
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