RESUMEN
The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 5' untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 5' UTR of GJB1 in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine GJB1 screening, as well as in NGS panels.
RESUMEN
X-linked Charcot-Marie-Tooth (CMTX) disease is a clinically heterogeneous hereditary motor and sensory neuropathy. The X-linked inheritance showed an absence of male-to-male transmission and a more severe disease phenotype in affected males compared to that in affected female. A missense mutation, Cys168Arg, was found in connexin 32 gene (Cx32/GJB1) from a patient with CMTX neuropathy. The familial history of this patient also suggested that the disease is X-linked CMT. Thus, we report a CMTX family having the novel Cys168Arg mutation in the Cx32 gene.