Mutations in a Gene Encoding a Novel SH3/TPR Domain Protein Cause Autosomal Recessive Charcot-Marie-Tooth Type 4C Neuropathy

Abstract

Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

“…Nerve conduction velocity measurements, morphometric analyses, and transcriptional analysis indicated the presence of the neuropathy already at 4 weeks of age, suggesting an early onset of the disease in Sh3tc2 ⌬Ex1/⌬Ex1 mice. The neuropathy was then slowly progressive; adult mutant mice presented MNCV and SNCV values Ϸ15 m/s below controls, which is a decrease comparable to the values recorded in CMT4C patients (4). Whereas CMT4C disease is commonly classified as ''demyelinating'' disease, we did not observe any signs of demyelination (e.g., myelin debris, Schwann cell onion bulbs, or macrophage infiltration) in the early stages of the disease in Sh3tc2 ⌬Ex1/⌬Ex1 mice.…”

“…During the last two decades, genetic studies have continuously documented new CMT4C cases (4,5,7,(12)(13)(14)(15). Although the recent identification of SH3TC2 as the gene mutated in CMT4C (4) immediately led to substantially improved clinical diagnostic and genetic counseling in the affected families, the functional role of the SH3TC2 protein in peripheral nerves remained unknown.…”

“…Electron microscopic analysis also demonstrated the presence of nonmyelinating Schwann cell complexes with abnormal cell processes and demyelinated and remyelinated axons surrounded by onion bulbs consisting of empty basal lamina sheaths (2-5). Disease severity and the age of onset vary in and between families, but usually the sensorimotor neuropathy can be detected in the first decade of life (4)(5)(6). In addition to the peripheral neuropathy, almost all patients affected by CMT4C develop early-onset severe scoliosis.…”

“…By homozygosity mapping and allele-sharing analysis, this interval was narrowed down to a 1.7-megabase region, leading to the identification of mutations in a thus far uncharacterized transcript called KIAA1985, or SH3TC2 (4). SH3TC2 encodes a protein of 1,288 aa containing two Src homology 3 (SH3) and 10 tetratricopeptide repeat (TPR) domains sharing no overall significant similarity to any other human protein with known function.…”

“…The presence of SH3 and TPR domains suggests that SH3TC2 could act as a scaffold protein. SH3TC2 is well conserved among vertebrate species, whereas no nonvertebrate orthologs were identified (4).…”