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

Hum Mol Genet. 2014 Oct 1;23(19):5171-87. doi: 10.1093/hmg/ddu240. Epub 2014 May 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Base Sequence
  • Binding Sites
  • Charcot-Marie-Tooth Disease / diagnosis
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / metabolism
  • Colforsin / pharmacology
  • Computational Biology
  • Conserved Sequence
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Databases, Genetic
  • Gene Expression
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Genetic Loci
  • Haplotypes*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Molecular Sequence Data
  • Motor Neurons / metabolism
  • Nucleotide Motifs
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Protein Binding
  • Proteins / genetics*
  • Rats
  • Regulatory Sequences, Nucleic Acid
  • Response Elements*
  • SOXE Transcription Factors / metabolism*
  • Schwann Cells / metabolism
  • Sequence Alignment
  • Severity of Illness Index
  • Transcription Factors / metabolism
  • Transcriptional Activation


  • Cyclic AMP Response Element-Binding Protein
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • SH3TC2 protein, human
  • SOXE Transcription Factors
  • Transcription Factors
  • Colforsin