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

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

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Department of Human Genetics.
Cellular and Molecular Pathology (CMP) Program.
Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Genome Analysis, Academic Medical Centre, Amsterdam, The Netherlands.
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-Gu, Seoul, Korea.
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, UK.
Department of Neurology Department of Pediatrics and Department of Physiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Waisman Center and Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA.
Department of Human Genetics Department of Neurology and Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, USA


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.

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