Clinical and biophysical characterization of 19 GJB1 mutations

Objective Charcot–Marie–Tooth disease type X1 ( CMTX 1), which is caused by mutations in the gap junction ( GJ ) protein beta‐1 gene ( GJB 1 ), is the second most common form of Charcot–Marie–Tooth disease ( CMT ). GJB 1 encodes the GJ beta‐1 protein ( GJB 1), which forms GJ s within the myelin sheaths of peripheral nerves. The process by which GJB 1 mutants cause neuropathy has not been fully elucidated. This study evaluated the biophysical characteristics of GJB 1 mutants and their correlations with the clinical features of CMTX 1 patients. Methods All patients with a validated GJB 1 mutation were assessed using the Charcot–Marie–Tooth disease neuropathy score version 2 ( CMTNS ). The impacts of the mutations on the biophysical functions of GJB 1 were characterized by assessing intracellular localization, expression patterns, and GJ Ca 2+ permeability. Result Nineteen GJB 1 mutations were identified in 24 patients with a clinical diagnosis of CMT . Six are novel mutations: p.L6S, p.I20F, p.I101Rfs*8, p.F153L, p.R215P, and p.D278V. Diverse pathological effects of the mutations were demonstrated, including reduced GJB 1 expression, intracellular mislocalization, and altered GJ functions. GJB 1 mutations that caused a complete loss of GJ Ca 2+ permeability appeared to be associated with an earlier disease onset, whereas those resulting in preservation of GJ permeability and with predominant cell membrane expression tended to have a later onset and a milder phenotype. Interpretation This study demonstrated that the degree of loss of GJ function caused by the GJB 1 mutations might contribute to the onset and severity of neuropathic symptoms in CMTX 1.