Identification of allelic variants of pendrin (SLC26A4) with loss and gain of function.

[pendred syndrome]

Pendrin is a multifunctional anion transporter that exchanges chloride and iodide in the thyroid , as well as chloride and bicarbonate in the inner ear , kidney and airways . Loss or reduction in the function of pendrin results in both syndromic (Pendred syndrome ) and non-syndromic (non-syndromic enlarged vestibular aqueduct (ns-EVA )) hearing loss . Factors inducing an up-regulation of pendrin in the kidney and the lung may have an impact on the pathogenesis of hypertension , chronic obstructive pulmonary disease (COPD ) and asthma . Here we characterize the ion transport activity of wild-type (WT ) pendrin and seven of its allelic variants selected among those reported in the single nucleotide polymorphisms data base (dbSNPs ), some of which were previously identified in a cohort of individuals with normal hearing or deaf patients belonging to the Spanish population .WT and mutated pendrin allelic variants were functionally characterized in a heterologous over-expression system by means of fluorometric methods evaluating the I (-)/Cl (-) and Cl (-)/OH (-) exchange and an assay evaluating the efflux of radiolabeled iodide .The transport activity of pendrin P 70 L , P 301 L and F 667 C is completely abolished ; pendrin V 609 G and D 687 Y allelic variants are functionally impaired but retain significant transport . Pendrin F 3 54 S activity is indistinguishable from WT , while pendrin V 88 I and G 740 S exhibit a gain of function .Amino acid substitutions involving a proline always result in a severe loss of function of pendrin . Two hyperfunctional allelic variants (V 88 I , G 740 S ) have been identified , and they may have a contributing role in the pathogenesis of hypertension , COPD and asthma .

Diseases
Validation

Diseases presenting "non-syndromic enlarged vestibular aqueduct" symptom

pendred syndrome

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