一个早逝型脊髓小脑共济失调家系ATXN3基因动态突变的研究

Instability Transmission of CAG Repeats of ATXN3 Gene in An Early-Death Family with Spinocerebellar Ataxia

目的:对早逝型脊髓小脑性共济失调(SCA)家系患者进行表型评价及分子遗传学诊断。方法:采用病例回顾和体检方法对家系进行调查,对存活并配合的家系成员进行基因检测。采用聚合酶链反应分别扩增SCA1、SCA2、SCA3/MJD、SCA6及SCA7致病基因的CAG重复序列,用8%变性聚丙烯酰胺凝胶电泳及荧光标记引物进行突变分析。结果:家系5代,目前共有14例发病,现患者仅存活4例,最早发病者信息不详,对其余13例进行表型评价。发病年龄33.5±7.71岁,病程11.6±4.03年,去世年龄46.0±7.16岁,遗传早现和遗传印记现象明显。对核心家系7例进行基因检测,5例为兄妹(包括3名患者),2例为其中2例患者的无症状未婚子女。3例患者SCA3/MJD致病基因ATXN3 CAG重复分别为72/29、74/29和73/29,2例患者子女分别为73/29和75/14,2例正常成员未携带异常重复突变,未发现SCA1、SCA2、SCA3/MJD、SCA6及SCA7基因中CAG突变性扩增。结论:ATXN3基因中CAG三核苷酸重复拷贝数的异常扩增是早逝型SCA3/MJD家系致病原因,CAG重复在传递过程中极不稳定是否导致该家系患者早逝,还有待进一步证实。2例未发病成员携带异常突变基因,预测将来可能发病。

Objective ： To evaluate the phenotypic characteristics and perform molecular genetics diagnosis on an early - death family with spinocerebellar ataxia （SCA）. Methods ： A retrospective survey and physical examination were adopted to investigate the characteristics of family. The polymerase chain reaction（PCR） was applied to amplify the CAG repeats sequence of the SCAI, SCA2, SCA3/MJD,SCA6 and SCA7 gene on survived and cooperative individuals of this family, and the CAG repeats were determined by 8% denaturing polyacrylamide gel electrophoresis and fluorescently - labeled primer. Results： Fourteen affected individuals were identified in this five - generation SCA family in which only 4 patients survived. The detail information of the earliest -onset individual was unclear; the phenotypes of the other 13 ones were evaluated. The average age of onset was 33.5 ± 7.71 years oht, and the duration was 11.6 ± 4.03 years, and the death age was 46.0 ± 7.16 years old. The characteristics of anticipation and genetic imprinting were obviously noticed. Seven individuals of the core family involved in gene detecting included 5 siblings （3 patients） and 2 unmarried asymptomatic offspring. For 3 patients, the CAG repeat of ATXN3 gene were 72/29, 74/29 and 73/29 respectively. For 2 offspring of the patients, they were 73/29 and 75/14. Abnormal repeat mutation was not detected in 2 unaffected individuals, and no mutation of SCA1, SCA2, SCA3/MJD, SCA6 and SCA7 gene were found. Conclusion ： CAG repeats mutation of ATXN3 gene could be the reason for the existence of the early - death SCA3/MJD family. It should be further investigated whether instability transmission of CAG repeats induces the early death in patients of this family. Two carrier of mutation ATXN3 gene would exhibit symptoms in the future.