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

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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