Transcriptional Control of SLC26A4 Is Involved in Pendred Syndrome and Nonsyndromic Enlargement of Vestibular Aqueduct ( DFNB4)

Tao Yang; Hilmar Vidarsson; Sandra Rodrigo-Blomqvist; Sally S Rosengren; Sven Enerbäck; Richard J.H Smith

doi:10.1086/518314

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Transcriptional Control of SLC26A4 Is Involved in Pendred Syndrome and Nonsyndromic Enlargement of Vestibular Aqueduct ( DFNB4)

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Transcriptional Control of SLC26A4 Is Involved in Pendred Syndrome and Nonsyndromic Enlargement of Vestibular Aqueduct ( DFNB4)

Tao Yang, Hilmar Vidarsson, Sandra Rodrigo-Blomqvist, Sally S Rosengren, Sven Enerbäck and Richard J.H Smith

American journal of human genetics, Vol.80(6), pp.1055-1063

2007

DOI: 10.1086/518314

PMID: 17503324

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Abstract

Although recessive mutations in the anion transporter gene SLC26A4 are known to be responsible for Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA), also known as “ DFNB4,” a large percentage of patients with this phenotype lack mutations in the SLC26A4 coding region in one or both alleles. We have identified and characterized a key transcriptional regulatory element in the SLC26A4 promoter that binds FOXI1, a transcriptional activator of SLC26A4. In nine patients with PS or nonsyndromic EVA, a novel c.−103T→C mutation in this regulatory element interferes with FOXI1 binding and completely abolishes FOXI1-mediated transcriptional activation. We have also identified six patients with mutations in FOXI1 that compromise its ability to activate SLC26A4 transcription. In one family, the EVA phenotype segregates in a double-heterozygous mode in the affected individual who carries single mutations in both SLC26A4 and FOXI1. This finding is consistent with our observation that EVA occurs in the Slc26a4 +/−; Foxi1 +/− double-heterozygous mouse mutant. These results support a novel dosage-dependent model for the molecular pathogenesis of PS and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery.

Details

Title: Subtitle: Transcriptional Control of SLC26A4 Is Involved in Pendred Syndrome and Nonsyndromic Enlargement of Vestibular Aqueduct ( DFNB4)
Creators: Tao Yang - Department of Otolaryngology–Head and Neck Surgery University of Iowa, Iowa City
Hilmar Vidarsson
Sandra Rodrigo-Blomqvist
Sally S Rosengren - and University of Connecticut Health Partners, West Hartford
Sven Enerbäck
Richard J.H Smith - Department of Otolaryngology–Head and Neck Surgery University of Iowa, Iowa City
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.80(6), pp.1055-1063
DOI: 10.1086/518314
PMID: 17503324
NLM abbreviation: Am J Hum Genet
ISSN: 0002-9297
eISSN: 1537-6605
Publisher: Elsevier Inc
Language: English
Date published: 2007
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984007178902771

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