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

The PDS gene encodes a transmembrane protein, known as pendrin, which funct ions as a transporter of iodide and chloride. Mutations in this gene are re sponsible for Pendred syndrome and autosomal recessive non-syndromic hearin g loss at the DFNB4 locus on chromosome 7q31. A screen of 20 individuals fr om the midwestern USA with non-syndromic hearing loss and dilated vestibula r aqueducts identified th ree people (15%) with PDS mutations, To determine whether PDS mutations in individuals with Pendred syndrome differ function ally from PDS mutations in individuals with non-syndromic hearing loss, we compared three common Pendred syndrome allele Variants (L236P, T416P and E3 84G), with three PDS mutations reported only in individuals with non-syndro mic hearing loss (V480D, V653A and 1490L/G497S). The mutations associated w ith Pendred syndrome have complete loss of pendrin-induced chloride and iod ide transport, while alleles unique to people with DFNB4 are able to transp ort both iodide and chloride, albeit at a much lower level than wild-type p endrin, We hypothesize that this residual level of anion transport is suffi cient to eliminate or postpone the onset of goiter in individuals with DFNB 4, We propose a model for pendrin function in the thyroid in which pendrin transports iodide across the apical membrane of the thyrocyte into the coll oid space.