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The gene for HMSN2C maps to 12q23-24

A region of neuromuscular disorders

From the Peripheral Neuropathy Research Laboratory (Drs. C.J. Klein, P.J.B. Dyck, and P.J. Dyck, D.M. Klein), Molecular Genetics Research Laboratory (Drs. Cunningham and Thibodeau, S.J. Hebbring and S.A. Anderson), and Division of Biostatistics (Dr. Schaid, E.J. Atkinson), Mayo Clinic and Mayo Foundation, Rochester, and Health Partners Medical Group (Dr. Litchy), Minneapolis, MN.

Address correspondence and reprint requests to Christopher J. Klein, MD, 200 First Street SW, Rochester, MN 55905; e-mail: klein.christopher{at}mayo.edu

Background: Hereditary motor and sensory neuropathy type 2C (HMSN2C, Charcot–Marie–Tooth 2C [CMT2C]) is an autosomal dominant motor and sensory neuropathy involving limb, diaphragm, vocal cord, and intercostal muscles.

Objective: To identify the chromosome localization for this disorder in one large American family of English and Scottish ethnicity.

Methods: Variable clinical severity led the authors to combine several approaches to accurately identify affected patients. Genome-wide two-point linkage analysis, high-definition mapping, and multipoint and recombinant haplotype analyses were performed. Mutation analysis of the triplet repeat region of ataxin-2 was also carried out.

Results: The initial genome-wide scan identified a region at 12q24, and fine mapping provided a maximal lod score of 4.73 (D12S1645 and D12S1583 at = 0.01 and 0, respectively). With multipoint analysis, a higher lod score of 5.17 was obtained and localized to the same region at 119.0 cM. Haplotype analysis narrowed the region to approximately 5.0 cM between D12S1646,D12S1330 and D12S105,D12S1339 (12q23.3-24.21). Ataxin-2, the gene responsible for spinocerebellar ataxia type 2 (SCA2), localizes to this region, but no triplet repeat expansion or point mutations within the repeat were found.

Conclusions: The gene for HMSN2C maps to 12q23-24. This region is associated with SCA2, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Further studies are needed to demonstrate the specific gene alteration and its relationship with nearby genes.

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