Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).

• 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.

Nyckelord

Alleles

Amino Acid Sequence

Animals

Binding Sites

COS Cells

Cercopithecus aethiops

Conserved Sequence

Electrophoretic Mobility Shift Assay

Female

Forkhead Transcription Factors

chemistry

genetics

metabolism

Genes

Reporter

Genetic Screening

Hearing Loss

diagnosis

genetics

Heterozygote

Humans

Luciferases

metabolism

Membrane Transport Proteins

genetics

Mice

Models

Genetic

Molecular Sequence Data

Mutation

Pedigree

Promoter Regions (Genetics)

Protein Binding

Protein Structure

Tertiary

Sequence Homology

Amino Acid

Siblings

Syndrome

Trans-Activators

chemistry

genetics

metabolism

Transcription

Genetic

Vestibular Aqueduct

pathology

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