Abstract
Charcot-Marie-Tooth disease is a demyelinating peripheral neuropathy and is a heterogeneous inherited disorder (40 loci have been described so far) affecting peripheral nerves. Two forms, CMT1A and CMTX, account for 60 and 15% of patients, respectively, with clear familial transmission (Boerkel et al., 2002). CMTX is caused by mutations in the GBJ1 gene encoding the synthesis of connexin 32 (Cx32, Bergoffen et al., 1993), which is a myelin protein related to PNS and CNS (Scherer et al., 1995). Cx32 is a membrane protein located in gap junctions, which forms hexameric hemichannels called connexons. However, the mechanism by which anomalies in connexin 32 affect myelination and function of PNS remains is still unclear. Here, we share our opinion that CamKinase are involved in the pathophysiology of CMTX and likely involve genomic instability caused by mutations in Gjb1.
Highlights
Charcot-Marie-Tooth disease is a demyelinating peripheral neuropathy and is a heterogeneous inherited disorder (40 loci have been described so far) affecting peripheral nerves
CMTX is caused by mutations in the GBJ1 gene encoding the synthesis of connexin 32 (Cx32, Bergoffen et al, 1993), which is a myelin protein related to PNS and CNS (Scherer et al, 1995)
We share our opinion that CamKinase are involved in the pathophysiology of CMTX and likely involve genomic instability caused by mutations in Gjb1
Summary
We recently showed that CamKII activity is overactivated in cells from a mouse model of CMTX involving mutations in Gjb (Mones et al, 2014) and in cells from CMTX1 patients (Mones et al, 2015) These cells presented centrosome overduplication and genomic instability. This cellular phenotype was corrected by treatment with CamKII inhibitors both in Gjb1-mutated mouse and human patient cells (Mones et al, 2014, 2015). These data suggest that anomalies of Cx32 due to GBJ1 mutations lead to unbalanced calcium homeostasis resulting in a genomic instability through the overactivation of CaMKII
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