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Pendred Syndrome in Two Galician Families: Insights into Clinical Phenotypes through Cellular, Genetic, and Molecular Studies

Unidade de Enfermedades Tiroideas e Metabólicas (F.P., D.A.-V., O.P.-G., L.D.-G., J.L.-A.), Department of Medicine, and Departments of Physiology (M.E.R.G.-R., S.B.B., C.V.A.) and Pathology (J.C.-T.), Fundación Pública Gallega de Medicina Genómica (L.L.), Molecular Medicine Unit, Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saude, University of Santiago de Compostela, Santiago de Compostela 15075, Spain; Instituto de Investigaciones Biomédicas "Alberto Sols" (M.J.O., R.M.C.), Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain; Fundación Pública Hospital Virxen da Xunqueira (P.A., J.L.-A.), Servicio Gallego de Salud, 15270 Cee, Spain; Department of Biochemistry (B.C.), Medical Centre for Postgraduate Education, 02-813 Warsaw, Poland; and Department of Medicine and Pediatrics (S.R.), Committees on Genetics and Molecular Medicine and J. P. Kennedy Mental Retardation and Developmental Disabilities Center, The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Joaquin Lado-Abeal, M.D., Ph.D., Unidade de Enfermedades Tiroideas e Metabólicas, Department of Medicine, University of Santiago de Compostela, C/ San Francisco sn, Santiago de Compostela 15705, Spain. E-mail: melado61{at}usc.es.

Context: We studied two families from Galicia (northwest Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T₃ (FT₃). In family B, some affected members showed deafness but not goiter.

Objective: Our objective was to identify the mutations causing PS and molecular mechanisms underlying the thyroid phenotypes.

Interventions: Interventions included extraction of DNA and of thyroid tissue.

Patients: Propositi and 10 members of the two families participated in the study.

Main Outcome Measures: Main outcome measures included SLC26A4 gene analysis, deiodinase activities in thyroid tissue, and c.416–1GA effects on SLC26A4 splicing. In addition, a primary PS thyrocyte culture, T-PS2, was obtained from propositus B and compared with another culture of normal human thyrocytes, NT, by Western blotting, confocal microscopy, and iodine uptake kinetics.

Results: Proposita A was heterozygous for c.578CT and c.279delT, presented with goiter, and had normal TSH and FT₃ but low FT₄ attributable to high type 1 and type 2 iodothyronine deiodinase activities in the goiter. Propositus B bore c.279delT and a novel mutation c.416–1GA; some deaf relatives were homozygous for c.416–1GA but did not present goiter. The c.279delT mutation was associated with identical haplotype in the two families. T-PS2 showed truncated pendrin retained intracellularly and high iodine uptake with low efflux leading to iodine retention.

Conclusions: c.279delT is a founder mutation in Galicia. Proposita A adapted to poor organification by increasing deiodinase activities in the goiter, avoiding hypothyroidism. Lack of goiter in subjects homozygous for c.416–1GA was due to incomplete penetrance allowing synthesis of some wild-type pendrin. Intracellular iodine retention, as seen in T-PS2, could play a role in thyroid alterations in PS.