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

Megan Hwa Brewer; Ki Hwan Ma; Gary W Beecham; Chetna Gopinath; Frank Baas; Byung-Ok Choi; Mary M Reilly; Michael E Shy; Stephan Züchner; John Svaren; Anthony Antonellis

doi:10.1093/hmg/ddu240

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

Journal article

Open access

Peer reviewed

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

Megan Hwa Brewer, Ki Hwan Ma, Gary W Beecham, Chetna Gopinath, Frank Baas, Byung-Ok Choi, Mary M Reilly, Michael E Shy, Stephan Züchner, John Svaren, …

Human molecular genetics, Vol.23(19), pp.5171-5187

10/01/2014

DOI: 10.1093/hmg/ddu240

PMCID: PMC4168306

PMID: 24833716

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Abstract

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.

Gene Expression

Computational Biology

Haplotypes

Humans

Regulatory Sequences, Nucleic Acid

Transcriptional Activation

Databases, Genetic

Molecular Sequence Data

Genetic Loci

Charcot-Marie-Tooth Disease - genetics

Nucleotide Motifs

Base Sequence

Conserved Sequence

Binding Sites

Charcot-Marie-Tooth Disease - metabolism

Genes, Reporter

Severity of Illness Index

Promoter Regions, Genetic

Response Elements

Colforsin - pharmacology

SOXE Transcription Factors - metabolism

Rats

Schwann Cells - metabolism

Gene Expression Regulation - drug effects

Motor Neurons - metabolism

Proteins - genetics

Transcription Factors - metabolism

Sequence Alignment

Animals

Alleles

Cyclic AMP Response Element-Binding Protein - metabolism

Protein Binding

Mice

Polymorphism, Single Nucleotide

Charcot-Marie-Tooth Disease - diagnosis

Details

Title: Subtitle: Haplotype-specific modulation of a SOX10/CREB response element at the Charcot-Marie-Tooth disease type 4C locus SH3TC2
Creators: Megan Hwa Brewer - Department of Human Genetics
Ki Hwan Ma - Cellular and Molecular Pathology (CMP) Program
Gary W Beecham - 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
Chetna Gopinath - Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, USA
Frank Baas - Department of Genome Analysis, Academic Medical Centre, Amsterdam, The Netherlands
Byung-Ok Choi - Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-Gu, Seoul, Korea
Mary M Reilly - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, UK
Michael E Shy - Department of Neurology Department of Pediatrics and Department of Physiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Stephan Züchner - 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
John Svaren - Waisman Center and Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA
Anthony Antonellis - Department of Human Genetics Department of Neurology and Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, USA antonell@umich.edu
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.23(19), pp.5171-5187
DOI: 10.1093/hmg/ddu240
PMID: 24833716
PMCID: PMC4168306
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: R01 NS075269 / NINDS NIH HHS R01 NS073748 / NINDS NIH HHS U54NS065712 / NINDS NIH HHS T32 GM007315 / NIGMS NIH HHS NS073748 / NINDS NIH HHS NS075269 / NINDS NIH HHS P30 HD003352 / NICHD NIH HHS
Language: English
Date published: 10/01/2014
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984020755902771

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