Objective: To clinically characterize and map the gene locus in a three-generation family with an X-linked adult-onset distal hereditary motor neuropathy.
Methods: Microsatellite markers spanning the juvenile distal spinal muscular atrophy (DSMAX) locus were genotyped and analyzed using genetic linkage analysis. The promoter, untranslated and coding region of the gap junction beta1 (GJB1) gene was sequenced. Nine positional candidate genes were screened for disease mutations using high-resolution melt (HRM) analysis.
Results: The family showed significant linkage to markers on chromosome Xq13.1-q21. Haplotype construction revealed a disease-associated haplotype between the markers DXS991 and DX5990. Sequence analysis excluded pathogenic changes in the coding and promoter regions of the GJB1 gene. Additional fine mapping in the family refined the DSMAX locus to a 1.44-cM interval between DXS8046 and DXS8114. HRM analysis did not identify disease-associated mutations in the coding region of nine candidate genes.
Conclusion: We have identified a family with adult-onset distal hereditary motor neuropathy that refines the locus reported for juvenile distal spinal muscular atrophy (DSMAX) on chromosome Xq13.1-q21. Exclusion of mutations in the coding and regulatory region of the GJB1 gene eliminated the CMTX1 locus as a cause of disease in this family. Nine positional candidate genes in the refined interval underwent mutation analysis and were eliminated as the pathogenic cause of DSMAX in this family. The syndrome in this family may be allelic to the juvenile distal spinal muscular atrophy first reported at this locus.