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High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

¹ Departments of Medical Sciences and ² Otorhinolaryngology and Ophthalmology, University of Milan, 20122 Milan, Italy, ³ Endocrine and Diabetes Unit, ⁴ Medical Genetic Unit and ⁵ Audiology Unit, Fondazione Policlinico IRCCS, 20122 Milan, Italy, ⁶ Department of Biomolecular Sciences and Biotechnology and CIMAINA, University of Milan, 20133 Milan, Italy

(Correspondence should be addressed to L Fugazzola; Email: l.fugazzola{at}policlinico.mi.it)

Objective: Pendred syndrome (PS) is characterized by the association of sensorineural hearing loss (SNHL) and a partial iodide organification defect at the thyroid level. It is caused by mutations in the SLC26A4 gene. The encoded transmembrane protein, called pendrin, has been found to be able to transport chloride and other anions.

Design: The aim of the present study was to characterize a family with PS, which shows a strong intrafamilial phenotypic variability, including kidney atrophy in one member. The age of disease-onset was significantly different in all three affected siblings, ranging from 2 to 21 years for thyroid alterations and from 1.5 to 11 years for SNHL.

Methods: Clinical and genetic studies were carried out in affected siblings. The functional activity of the novel duplication found was studied by a fluorimetric method in a human renal cell line (HEK293 Phoenix) in which the protein was overexpressed.

Results: All three siblings were found to be compound heterozygotes for the missense mutation (1226G>A, R409H) and for a novel 11 bp duplication (1561_1571CTTGGAATGGC, S523fsX548). The latter mutation creates a frame shift leading to the loss of the entire carboxy-terminus domain. Functional studies of this mutant demonstrated impaired transport of chloride and iodide when expressed in HEK 293 Phoenix cells, when compared with wild type pendrin.

Conclusions: A novel 11 bp duplication was found in a family with Pendred syndrome, showing a high intrafamilial phenotypic variability. An impaired transmembrane anionic transport of the mutated SLC26A4 protein was demonstrated in functional studies using a heterologous cell system.

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				A. Pera, S. Dossena, S. Rodighiero, M. Gandia, G. Botta, G. Meyer, F. Moreno, C. Nofziger, C. Hernandez-Chico, and M. Paulmichl Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA PNAS, November 25, 2008; 105(47): 18608 - 18613. [Abstract] [Full Text] [PDF]