Two novel SH3TC2 mutations predispose to Charcot-Marie-Tooth disease type 4C by mistargeting away from TFRC.

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive form of demyelinating neuropathy caused by the biallelic pathogenic mutations in the SH3TC2 gene and characterized by progressive scoliosis, muscular atrophy, distal weakness, and reduced nerve conduction velocity. Here, we report two novel SH3TC2 mutations (c.452dupT and c.731 + 1G > T) from a proband with typical clinical manifestations of CMT4C. Splicing assay reveals the SH3TC2 c.731 + 1G > T mutation leads to a 58-nucleotide (nt) deletion from the downstream of exon 6 causing a frameshift and resulting in an early termination of protein expression. Protein expression assay indicates SH3TC2 c.452dupT mutant is degraded by both the nonsense mediated decay (NMD) and the ubiquitin-proteasome pathway. Moreover, our intracellular immunofluorescence, co-immunoprecipitation, liquid chromatography mass spectrometry and molecular docking describe that SH3TC2 interacts with the transferrin receptor protein 1 (TFRC) encoding a cell surface receptor playing a crucial role in mediating iron homeostasis. Interestingly, both the two novel SH3TC2 mutations present in our CMT4C patients are defective in the association with TFRC. Our study reveals the pathogenesis of these two novel SH3TC2 mutations and indicates that the SH3TC2-TFRC interaction is relevant for peripheral nerve pathophysiology, thus provides a novel insight into the pathophysiology of CMT4C neuropathy.