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Loss-of-function mutations in the Src homology 3 (SH3) domain and tetratricopeptide repeats 2 ( SH3TC2 ) gene cause autosomal recessive demyelinating Charcot–Marie–Tooth neuropathy. The SH3TC2 protein has been implicated in promyelination signaling through axonal neuregulin-1 and the ERBB2 Schwann cell receptor. However, little is known about the transcriptional regulation of the  SH3TC2  gene. We performed computational and functional analyses that revealed two  cis -acting regulatory elements at  SH3TC2 —one at the promoter and one ∼150 kb downstream of the transcription start site. Both elements direct reporter gene expression in Schwann cells and are responsive to the transcription factor SOX10, which is essential for peripheral nervous system myelination. The downstream enhancer harbors a single-nucleotide polymorphism (SNP) that causes an ∼80% reduction in enhancer activity. The SNP resides directly within a predicted binding site for the transcription factor cAMP response element binding protein (CREB), and we demonstrate that this regulatory element binds to CREB and is activated by CREB expression. Finally, forskolin induces  Sh3tc2  expression in rat primary Schwann cells, indicating that  SH3TC2  is a CREB target gene. These findings prompted us to determine if SNP genotypes at  SH3TC2  are associated with differential phenotypes in the most common demyelinating peripheral neuropathy, CMT1A. Interestingly, this revealed several associations between SNP alleles and disease severity. In summary, our data indicate that  SH3TC2  is regulated by the transcription factors CREB and SOX10, define a regulatory SNP at this disease-associated locus and reveal  SH3TC2  as a candidate modifier locus of CMT disease phenotypes.

Haplotype-specific modulation of a SOX10/CREB response element at the Charcot–Marie–Tooth disease type 4C locus SH3TC2