title: Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).
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.
authors.affiliation: Department of Otolaryngology-Head and Neck, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Hilmar
authors.initials: H
authors.lastname: Vidarsson
authors.forename: Sandra
authors.initials: S
authors.lastname: Rodrigo-Blomqvist
authors.forename: Sally S
authors.initials: SS
authors.lastname: Rosengren
authors.forename: Sven
authors.initials: S
authors.lastname: Enerback
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D005820:Genetic Testing; D034381:Hearing Loss / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D035781:Siblings; D000076988:Sulfate Transporters; D013577:Syndrome; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014723:Vestibular Aqueduct / Q000473:pathology*
chemical_list: C477894:FOXI1 protein, human; D051858:Forkhead Transcription Factors; C508689:Foxi1 protein, mouse; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; D015534:Trans-Activators; D008156:Luciferases