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Human Molecular Genetics, 2002, Vol. 11, No. 21 2625-2633
© 2002 Oxford University Press

Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome

Pnina Rotman-Pikielny1,{dagger}, Koret Hirschberg6,{dagger}, Padma Maruvada1, Koichi Suzuki4, Ines E. Royaux2, Eric D. Green2, Leonard D. Kohn5, Jennifer Lippincott-Schwartz3 and Paul M. Yen1,*

1Clinical Endocrinology Branch, NIDDK, 2Genome Technology Branch, NHGRI, and 3Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA, 4National Institute of Infectious Diseases, Higashimurayama, Tokyo, Japan, 5Department of Biomedical Sciences and Edison Biotechnology Institute, Ohio University College of Osteopathic Medicine, Athens, Ohio, USA and 6Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Received June 7, 2002; Accepted July 27, 2002

Pendred syndrome is a major cause of congenital deafness, goiter and defective iodide organification. Mutations in the transmembrane protein, pendrin, cause diminished export of iodide from thyroid follicular cells to the colloid and are associated with the syndrome. We used green fluorescent protein (GFP) chimeras of wild-type (WT) pendrin and three common natural mutants (L236P, T416P and G384) to study their intracellular trafficking in living cells. Time-lapse imaging, dual color labeling and fluorescent recovery after photobleaching (FRAP) studies demonstrated that GFP–WT pendrin targets to the plasma membrane. In contrast, all three mutant pendrins were retained in the endoplasmic reticulum (ER) in co-localization studies with ER and Golgi markers. The ER retention of L236P appeared to be selective as this mutant did not prevent a viral membrane protein, VSVGtsO45 or wild-type pendrin from targeting the plasma membrane. These findings suggest that ER retention and defective plasma membrane targeting of pendrin mutants play a key role in the pathogenesis of Pendred syndrome.

* To whom correspondence should be addressed at: Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institutes of Health, Building 10, Room 8D12, Bethesda, Maryland 20892; Tel: +1 3015946797; Fax: +1 3014024136; Email: pauly{at}intra.niddk.nih.gov

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be treated as joint First Authors.


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