Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease

Objective: To characterize a large family with X-linked Charcot-Marie-Tooth (CMT) neuropathy without mutations in the gap junction protein B1 (GJB1) gene, which has an unusual phenotype that is different in some aspects from classic CMTX1. Methods: We tested CMT families consistent with X-linked inheritance for GJB1 mutations. We compared the largest family (CMT623) without GJB1 mutation and with linkage excluding the CMTX1 locus to CMTX1 and normal individuals. Results: Only 51% of probable X-linked CMT families had mutations in GJB1. Family CMT623 shows linkage to Xq26.3-q27.1 (lod score z = 6.58), a region within the previously identified locus for CMTX3, Xq26-q28. Unlike CMTX1, affected males in family CMT623 report pain and paraesthesia before the onset of sensory loss, and women are usually asymptomatic. As in CMTX1, affected males have widely ranging intermediate motor conduction velocities. The coding regions of 14 positional candidate genes within the narrowed CMTX3 locus have been excluded for a pathogenic role in the disease. Conclusion: This study is the first to confirm the CMTX3 locus and to refine the genetic interval to a 5.7-Mb region flanked by the markers DXS1041 and DXS8106. GJB1 mutation-negative forms of X-linked CMT, such as CMTX3, may account for a significant proportion of X-linked CMT.