SH3TC2 – Charcot-Marie-Tooth Disease Type 4C

Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset autosomal recessive demyelinating neuropathy characterized by early-onset motor and sensory neuropathy, scoliosis, distal muscle weakness, and reduced nerve conduction velocity. Biallelic pathogenic variants in SH3TC2 underlie CMT4C, with an estimated prevalence of 30% among undiagnosed CMT4 patients and reports across diverse populations including European, Japanese, Indian, and Chinese cohorts.

Extensive genetic studies have identified SH3TC2 as the causative gene for CMT4C. Initial homozygosity mapping and allele-sharing in 12 families refined the locus to 5q23-q33 and revealed eight protein-truncating and three nonconservative missense mutations in SH3TC2, each segregating in homozygous or compound heterozygous states with disease ([PMID:14574644]). Subsequent screening of 43 demyelinating AR-CMT patients uncovered SH3TC2 mutations in 11 index cases (30% frequency), including nonsense, splice-site, synonymous (predicted splicing), and frameshift variants ([PMID:27231023]).

The variant spectrum in SH3TC2 includes loss-of-function alleles (nonsense, frameshift, splice) and missense changes affecting conserved residues. A recurrent missense variant c.1585C>T (p.Arg529Cys) has been detected in unrelated families ([PMID:14574644]). Other recurrent alleles include c.2860C>T (p.Arg954Ter) and c.3325C>T (p.Arg1109Ter), reflecting founder effects in European and Asian populations.

Segregation analysis across multiple families demonstrates clear co-segregation of SH3TC2 mutations with CMT4C phenotype. In the largest cohort (14 patients), all homozygous or compound heterozygous individuals manifested demyelinating neuropathy with scoliosis in 79% and cranial nerve involvement in 64%, supporting autosomal recessive inheritance and high penetrance ([PMID:27231023]).

Functional studies corroborate the pathogenic mechanism. Sh3tc2 knockout mice develop hypomyelination, reduced motor/sensory nerve conduction velocities, and disorganized nodes of Ranvier, mirroring human CMT4C ([PMID:19805030]). Cellular assays show that disease-causing SH3TC2 mutations disrupt Rab11-dependent endosomal recycling and impair SH3TC2 localization to the recycling endosome and plasma membrane, revealing a defect in Schwann cell myelin maintenance ([PMID:20028792]).

Collectively, genetic and experimental evidence definitively establishes SH3TC2 as the gene for CMT4C. Comprehensive variant screening and phenotypic correlation enable molecular diagnosis, carrier testing, and genetic counseling. Emerging gene therapy approaches targeting Schwann cells hold promise for future treatment.

Key Take-home: SH3TC2 biallelic loss-of-function and critical missense variants cause autosomal recessive CMT4C, and functional assays substantiate a haploinsufficiency mechanism disrupting Schwann cell myelination.

References

• Am J Hum Genet • 2003 • Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. PMID:14574644
• J Peripher Nerv Syst • 2016 • Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4). PMID:27231023
• Proc Natl Acad Sci U S A • 2009 • SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system. PMID:19805030
• Hum Mol Genet • 2010 • Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C. PMID:20028792

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