Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4)

Daryl A. Scott, Rong Wang, Trisha M. Kreman, Mike Andrews, Joshua M. McDonald, Jeffrey R. Bishop, Richard J H Smith, Lawrence P. Karniski, Val C. Sheffield

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

Abstract

The PDS gene encodes a transmembrane protein, known as pendrin, which functions as a transporter of iodide and chloride. Mutations in this gene are responsible for Pendred syndrome and autosomal recessive non-syndromic hearing loss at the DFNB4 locus on chromosome 7q31. A screen of 20 individuals from the midwestern USA with non-syndromic hearing loss and dilated vestibular aqueducts identified three people (15%) with PDS mutations. To determine whether PDS mutations in individuals with Pendred syndrome differ functionally from PDS mutations in individuals with non-syndromic hearing loss, we compared three common Pendred syndrome allele variants (L236P, T416P and E384G), with three PDS mutations reported only in individuals with non-syndromic hearing loss (V480D, V653A and I490L/G497S). The mutations associated with Pendred syndrome have complete loss of pendrin-induced chloride and iodide transport, while alleles unique to people with DFNB4 are able to transport both iodide and chloride, albeit at a much lower level than wild-type pendrin. We hypothesize that this residual level of anion transport is sufficient to eliminate or postpone the onset of goiter in individuals with DFNB4. We propose a model for pendrin function in the thyroid in which pendrin transports iodide across the apical membrane of the thyrocyte into the colloid space.

Original languageEnglish (US)
Pages (from-to)1709-1715
Number of pages7
JournalHuman molecular genetics
Volume9
Issue number11
DOIs
StatePublished - Jul 1 2000

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