Characterisation of the Pendred syndrome gene

Pendred syndrome is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid enlargement. Phenotypic heterogeneity is observed in affected individuals particularly, with regard to the severity of thyroid dysfunction. Mutations in the PDS (SLC26A4) gene on chromosome 7q31, have been shown to cause Pendred syndrome. PDS is expressed in the inner ear, thyroid and kidney and encodes a transmembrane protein, pendrin, with anion transporter properties. Pendrin localises to the apical membrane of thyroid follicular cells and is thought to enable efflux of iodide into the follicle lumen. The role of pendrin within the inner ear is unclear. This thesis has sought to expand the molecular characterisation of the PDS gene and investigate the properties of mutant alleles in Pendred syndrome.;Work to analyse the expression profile of PDS using the mouse as a model was undertaken. A partial sequence of the PDS orthologue (pds) was identified, from which probes were designed and used in in situ hybridisation experiments.;Mutational analysis of genomic DNA was performed in an extensive panel of subjects with phenotypes observed in Pendred syndrome. The results from the direct sequencing of the PDS coding regions emphasised genotype/phenotype complexity. The inability to detect mutations in a number of subjects point to the likely existence of mutations within non-coding regions of PDS and/or genomic rearrangements.;To understand the impact of PDS mutations on pendrin function PDS cDNA constructs were generated and expressed in cultured cells. A functional iodide efflux assay was developed to assess pendrin function. The pendrin mutants studied showed different levels of dysfunction and indicate that additional genetic and/or environmental modifying factors appear to influence the Pendred syndrome phenotype