-459C>T point mutation in 5' non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy.

Charcot-Marie-Tooth (CMT) neuropathy is inherited with genetic and clinical heterogeneity. The X-linked form (CMTX) is linked to mutations in the GJB1 gene. However, the genotype-phenotype correlation between variants in the non-coding region of GJB1 gene and CMTX is unclear. We found two structural variants (-459C>T and -713G>A) in the 5' non-coding region of a transcript (Ref seq ID: NM_000166) of the GJB1 gene and explored its association with CMTX in two Chinese families. All family members who carried the -459C>T variant either were symptomatic or had abnormal electrophysiological studies compatible with CMTX, whereas all the non-symptomatic family members who had normal electrophysiological studies and 10 healthy unrelated controls did not have this variant. The other variant in the 5'-flanking region of the gene was found to be a benign polymorphism, although it had been earlier reported to be associated with CMTX in a Taiwanese family. Secondary structure prediction analysis of mutant mRNA using M fold and RNA structure softwares indicates that the -459C>T mutation may reduce translation efficiency of the GJB1 gene by changing its 5'-untranslated region secondary structure and abolishing the internal ribosome entry site at the initialization of its translation in Schwann cells. Our study can help clarify the causal mutations of CMTX in the non-protein coding region of GJB1.