Molecular analysis of a new type of hereditary motor sensory neuropathy with proximal dominant involvement

我们报告了日本冲绳的常染色体显性遗传性运动和感觉神经病(HMSNP)，其特征是成人起病的近端显性神经源性萎缩，明显的感觉受累，痛性肌肉痉挛，束束，反射障碍，以及肌酸激酶水平升高、高脂血症和糖尿病的高发生率(HMSNP-Okinawa)。通过连锁不平衡定位和单倍型分析，将该基因定位在染色体3q13.1上。标记D3S1591的共同等位基因的存在和该病的地理特异性提示了连锁不平衡和该病的单一创建者。我们构建了3Q12-13区域(约1.3Mb)的BAC/PAC重叠群，并通过HMSNP-Okinawa患者和健康家系成员的DNA序列比较，筛选出位于该区域的候选基因。我们在这些患者中没有发现常见的杂合性突变或候选基因的任何特定缺失。我们在本州岛滋贺县发现了一个临床特征几乎相同的HMSNP-冲绳新家系(HMSNP-Shiga)。除第一个HMSNP-Shiga家系外，我们还发现了两个新的HMSNP-Shiga家系，并在征得知情同意后，用400个大卫星DNA标记对所有染色体进行了连锁定位。也与HMSNP-Okinawa相关的3Q12-13区域的一些DNA标记显示Lod评分为3或以上。单倍型分析显示HMSNP-ShigA家系成员中常见的单倍型。这些结果表明，HMSNP-冲绳和志贺的致病基因被定位在共同的CH3区域。HMSNP的临床特征与家族性ALS和Kennedy-Alter-Sung综合征相似。我们相信，克隆疾病基因和阐明HMSNP的病理生理机制将有助于解决其他形式的神经原性肌萎缩的机制。

We have reported autosomal dominant hereditary motor and sensory neuropathy with proximal dominant involvement (HMSNP) characterized by adult onset proximal dominant neurogenic atropfy, obvious sensory involvement, painful muscle cramp, fasciculations, areflexia, and high incidences of elevated creatine kinase levels, hyperlipidemia and diabetes mellitus in Okinawa, Japan (HMSNP-Okinawa). We have mapped the gene locus to chromosome 3q13.1 by linkage disequilibrium mapping and haplotype analysis. The presence of a common allele of marker D3S1591 and the geographical specificity of the disease suggested linkage disequilibrium and a single founder of this disease. We constructed BAC/PAC contig in the region of 3Q12-13 (about 1.3 Mb) and screed the candidate genes located in the region through comparison of DNA sequence between patients with HMSNP-Okinawa and healthy family members. We have not found common heterozygous mutations or any specific deletion of the candidate genes in the patientsWe found a new family with almost identical clinical features of HMSNP-Okinawa in Shiga prefecture, Honshu Island (HMSNP-Shiga). In addition of the first HMSNP-Shiga family, we found two new families with HMSNP-Shiga and performed linkage mapping with 400 macrosatellite DNA markers covering all chromosomes after informed consent obtained. Some DNA markers on 3q12-13 region, which were also associated with HMSNP-Okinawa, showed lod score 3 or over. Haplotype analysis showed common haplotype in the affected family members with HMSNP-Shiga. These results suggest that the causative genes for HMSNP-Okinawa and Shiga are mapped to common ch3 region. The clinical features of HMSNP resembled those of familial ALS and Kennedy-Alter-Sung syndrome. We believe that cloning of the disease gene and clarification of the pathophysiology of HMSNP will contribute to resolution of the mechanisms of other froms of neurogenic muscular atrophy