Maciel P, Gaspar C, DeStefano A L, Silveira I, Coutinho P, Radvany J, Dawson D M, Sudarsky L, Guimarães J, Loureiro J E
Centre for Research in Neuroscience, McGill University, Montreal General Hospital Research Institute, Québec, Canada.
Am J Hum Genet. 1995 Jul;57(1):54-61.
Machado-Joseph disease (MJD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene on 14q32.1. We confirmed the presence of this expansion in 156 MJD patients from 33 families of different geographic origins: 15 Portuguese Azorean, 2 Brazilian, and 16 North American of Portuguese Azorean descent. Normal chromosomes contain between 12 and 37 CAG repeats in the MJD gene, whereas MJD gene carriers have alleles within the expanded range of 62-84 CAG units. The distribution of expanded alleles and the gap between normal and expanded allele sizes is either inconsistent with a premutation hypothesis or most (if not all) of the alleles we studied descend from a common ancestor. There is a strong correlation between the expanded repeat size and the age at onset of the disease as well as the clinical presentation. There is mild instability of the CAG tract length with transmission of the expanded alleles; both increase and decrease in size between parents and progeny occur, with larger variations in male than in female transmissions. Together, these effects can partly explain the variability of age at onset and of phenotypic features in MJD; however, other modifying factors must exist.
马查多-约瑟夫病（MJD）与位于14q32.1的一个新基因中CAG三核苷酸重复序列的扩增有关。我们在来自不同地理区域的33个家族的156例MJD患者中证实了这种扩增的存在：15例葡萄牙亚速尔人、2例巴西人以及16例有葡萄牙亚速尔人血统的北美患者。正常染色体在MJD基因中含有12至37个CAG重复序列，而MJD基因携带者的等位基因在62 - 84个CAG单位的扩增范围内。扩增等位基因的分布以及正常和扩增等位基因大小之间的差距要么与前突变假说不一致，要么我们研究的大多数（如果不是全部）等位基因都来自一个共同祖先。扩增重复序列的大小与疾病的发病年龄以及临床表现之间存在很强的相关性。随着扩增等位基因的传递，CAG序列长度存在轻度不稳定性；亲子代之间大小既有增加也有减少，男性传递中的变化比女性传递中的变化更大。这些效应共同可以部分解释MJD发病年龄和表型特征的变异性；然而，必定还存在其他修饰因素。
