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

我们报道了常染色体显性遗传性运动和感觉神经病变伴近端显性受累（HMSNP），其特征是成人发病的近端显性神经萎缩，明显的感觉受累，疼痛性肌肉痉挛，束状肌痉挛，反射性松弛，高发生率的肌酸激酶水平升高，高脂血症和糖尿病在日本冲绳（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连锁不平衡和该病的单一创始人。我们构建了位于3Q12-13区域（约1.3 Mb）的BAC/PAC序列，并通过比较HMSNP-Okinawa患者与健康家庭成员的DNA序列，筛选了位于该区域的候选基因。本研究在本州岛滋贺县发现了一个具有几乎相同临床特征的HMSNP-Okinawa新家族（HMSNP-Shiga）。除了第一个hmsnp -志贺家族外，我们还发现了两个新的hmsnp -志贺家族，并在获得知情同意后，对覆盖所有染色体的400个大卫星DNA标记进行了连锁定位。在与HMSNP-Okinawa相关的3q12-13区域，部分DNA标记的lod评分在3分以上。单倍型分析显示，hsnp -志贺家族成员中存在共同的单倍型。这些结果表明，hsnp -冲绳和志贺的致病基因定位在共同的ch3区。HMSNP的临床特征与家族性ALS和Kennedy-Alter-Sung综合征相似。我们相信，该疾病基因的克隆和HMSNP病理生理学的阐明将有助于解决其他形式的神经源性肌萎缩的机制

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