Richter A, Poirier J, Mercier J, Julien D, Morgan K, Roy M, Gosselin F, Bouchard J P, Melançon S B
Service de Génétique Médicale, Hôpital Sainte-Justine, Montreal, Quebec, Canada.
Am J Med Genet. 1996 Sep 6;64(4):594-601. doi: 10.1002/(SICI)1096-8628(19960906)64:4<594::AID-AJMG13>3.0.CO;2-C.
The gene for Friedreich ataxia (FRDA), an autosomal-recessive neurodegenerative disease, remains elusive. The current candidate region of about 150 kb lies between loci FR2 and F8101 near the D9S15/D9S5 linkage group at 9q13-21.1. Linkage homogeneity between classical FRDA and a milder, slowly progressive Acadian variant (FRDA-Acad) has been demonstrated. An extended D9S15-D9S5 haplotype (C6) predominates in FRDA-Acad chromosomes from Louisiana. We studied 10 Acadian families from New Brunswick, Canada. In eight families, affected individuals conformed to the clinical description of FRDA-Acad; in one, 2 sibs presented with spastic ataxia (SPA-Acad). In the last family, 2 sibs had FRDA-Acad, and one had SPA-Acad. We found that SPA-Acad is linked to the FRDA gene region. The C6 haplotype and a second major haplotype (B7) were identified. The same ataxia-linked haplotypes segregated with both FRDA-Acad and SPA-Acad in two unrelated families. The parental origins of these haplotypes were different. Our observation of different phenotypes associated with the same combination of haplotypes may point to the influence of the parent of origin on gene expression, indicate the effect of modifier genes, or reflect the presence of different mutations on the same haplotypes. Our findings underline the need to investigate families with autosomal-recessive ataxias for linkage to the FRDA region, despite lack of key diagnostic manifestations such as cardiomyopathy or absent deep-tendon reflexes.
弗里德赖希共济失调（FRDA）是一种常染色体隐性神经退行性疾病，其致病基因仍不清楚。目前约150kb的候选区域位于9q13 - 21.1处D9S15/D9S5连锁群附近的FR2和F8101位点之间。经典型FRDA与一种较轻的、进展缓慢的阿卡迪亚变异型（FRDA - Acad）之间的连锁同质性已得到证实。一种扩展的D9S15 - D9S5单倍型（C6）在来自路易斯安那州的FRDA - Acad染色体中占主导地位。我们研究了来自加拿大新不伦瑞克省的10个阿卡迪亚家族。在8个家族中，受影响个体符合FRDA - Acad的临床描述；在1个家族中，2名同胞表现为痉挛性共济失调（SPA - Acad）。在最后一个家族中，2名同胞患有FRDA - Acad，1名患有SPA - Acad。我们发现SPA - Acad与FRDA基因区域连锁。鉴定出了C6单倍型和第二种主要单倍型（B7）。在两个不相关的家族中，相同的共济失调连锁单倍型与FRDA - Acad和SPA - Acad均发生分离。这些单倍型的亲本来源不同。我们观察到相同单倍型组合与不同表型相关，这可能表明亲本来源对基因表达的影响，提示修饰基因的作用，或反映相同单倍型上存在不同突变。我们的研究结果强调，尽管缺乏心肌病或深部腱反射消失等关键诊断表现，但仍有必要对常染色体隐性共济失调家族进行与FRDA区域的连锁研究。
