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Mutations of the PDS Gene, Encoding Pendrin, Are Associated with Protein Mislocalization and Loss of Iodide Efflux: Implications for Thyroid Dysfunction in Pendred Syndrome

Division of Medical Genetics, Department of Genetics (J.P.T., R.C.T.), University of Leicester, Leicester LE1 7RH, United Kingdom; and Division of Clinical Sciences (North) (R.A.M., P.F.W., A.P.W.), University of Sheffield, Northern General Hospital, Sheffield S5 7AU United Kingdom

Address all correspondence and requests for reprints to: Richard C. Trembath, Division of Medical Genetics, Departments of Medicine and Genetics, Adrian Building, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom. E-mail: . rtrembat{at}hgmp.mrc.ac.uk

Abstract

Pendred syndrome (PDS) is an autosomal recessive disorder characterized by deafness and goiter. Phenotypic heterogeneity is observed in affected individuals, and thyroid dysfunction is particularly variable. The syndrome is caused by mutations in the PDS (SLC26A4) gene, encoding an anion transporter pendrin, which localizes to the apical membrane of thyroid follicular cells. PDS is thought to enable efflux iodide into the follicle lumen. More than 50 diseases causing mutations of PDS have been reported. Here we have investigated the effect of nine PDS missense mutations on pendrin localization and iodide transport with the view to understanding their functional impact. As demonstrated by transient expression of green fluorescent protein-tagged pendrin mutant constructs in mammalian cell lines, appropriate trafficking to the plasma membrane was observed for only two mutants. The remaining PDS mutants appear to be retained within the endoplasmic reticulum following transfection. Iodide efflux assays were performed using human embryonic kidney 293 cells transfected with mutant pendrin and cotransfected with sodium iodide transporter to provide a mechanism of iodide uptake. The results indicated loss of pendrin iodide transport for all mislocalizing mutations. However, PDS mutants are associated with variable thyroid dysfunction in affected subjects. We concluded that additional genetic and/or environmental factors influence the thyroid activity in Pendred syndrome.

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