SH3TC2 – Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease type 4C (CMT4C) is an early-onset autosomal recessive demyelinating peripheral neuropathy characterized by childhood gait disturbance, progressive scoliosis, cranial nerve involvement, and markedly reduced nerve conduction velocities (<34 m/s) (PMID:16924012)(PMID:19805030).

Genetic studies in consanguineous and outbred cohorts have identified biallelic SH3TC2 mutations in over 50 unrelated probands from ≥12 families, with segregation in multiple pedigrees (PMID:16924012) and additional case series of 14 patients demonstrating AR inheritance and compound heterozygosity (PMID:22462672). Population screening in 103 Japanese demyelinating CMT patients revealed SH3TC2 mutations in 2 patients (5.5%) (PMID:23466821), and a Chinese cohort identified 7 likely pathogenic variants in 8 patients, yielding a CMT4C frequency of 4.2% (PMID:33643188). A French series of 3,412 IPN patients with hearing loss also reported SH3TC2 truncating alleles in demyelinating cases (PMID:31393079).

The variant spectrum exceeds 100 distinct pathogenic alleles, predominantly loss-of-function: nonsense (e.g., c.2860C>T (p.Arg954Ter)), frameshift, splice-site, and rare missense changes affecting conserved residues or splicing (PMID:16924012)(PMID:35207700). The recurrent p.Arg954Ter founder mutation accounts for ~60% of CMT4C alleles in European and Roma populations (PMID:31634715).

Functional characterization demonstrates that Sh3tc2 knockout mice develop progressive hypomyelination, decreased motor and sensory NCVs, and disorganized nodes of Ranvier concordant with human pathology (PMID:19805030). Wild-type SH3TC2 binds Rab11 and localizes to recycling endosomes in Schwann cells, whereas disease-causing missense and truncating mutants mislocalize and fail to support transferrin receptor recycling (PMID:20028792).

Mechanistically, SH3TC2 loss-of-function disrupts Rab11-mediated endosomal recycling of integrin-α6 and other myelin-associated cargo, impairing Schwann cell-axon interactions and myelin maintenance, leading to demyelination and scoliosis hallmarking CMT4C (PMID:19805030).

Clinically, testing for SH3TC2 variants—including c.2860C>T (p.Arg954Ter) and other LoF alleles—should be integrated into AR-CMT gene panels, with consideration of CNV analysis for exon deletions. Early molecular diagnosis enables genetic counselling, physiotherapy planning, and enrollment in emerging gene-replacement trials (PMID:37641403).

No substantive conflicting reports have been described. The breadth of familial segregation, multi-ethnic replication, and concordant functional models support a Definitive gene–disease association.

Key take-home: SH3TC2 is definitively implicated in autosomal recessive CMT4C via loss-of-function variants causing Schwann cell endosomal trafficking defects, informing diagnostic strategies and gene therapy development.

References

• Neurology • 2006 • Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations. PMID:16924012
• Proceedings of the National Academy of Sciences of the United States of America • 2009 • SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system. PMID:19805030
• Human Molecular Genetics • 2010 • Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C. PMID:20028792
• Journal of human genetics • 2013 • Molecular analysis of the genes causing recessive demyelinating Charcot-Marie-Tooth disease in Japan. PMID:23466821
• Journal of the peripheral nervous system : JPNS • 2012 • Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C. PMID:22462672
• Frontiers in neurology • 2021 • Characteristics of Clinical and Electrophysiological Pattern in a Large Cohort of Chinese Patients With Charcot-Marie-Tooth 4C. PMID:33643188
• Molecular genetics & genomic medicine • 2019 • Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French series. PMID:31393079
• Molecular Therapy : the journal of the American Society of Gene Therapy • 2023 • AAV9-mediated SH3TC2 gene replacement therapy targeted to Schwann cells for the treatment of CMT4C. PMID:37641403

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