Functional characterization of pendrin mutations found in the Israeli and Palestinian populations.

[pendred syndrome]

Pendrin is a transport protein exchanging chloride for other anions , such as iodide in the thyroid gland or bicarbonate in the inner ear . Mutations in the SLC 26 A 4 gene encoding for pendrin are responsible for both syndromic (Pendred syndrome ) and non-syndromic (non-syndromic enlarged vestibular aqueduct , EVA ) hearing loss . Besides clinical and radiological assessments , molecular and functional studies are essential for the correct diagnosis of Pendred syndrome and non-syndromic EVA . While a broad spectrum of mutations found in the Caucasian population has been functionally characterized , little is known about mutations specifically occurring in the populations of the Middle East . Here we show the characterization of the ion transport activity of three pendrin mutations previously found in deaf patients with EVA in the Israeli Jewish and Palestinian Arab populations , i .e . V 239 D , G 334 V X 335 and I 487 Y FSX 39 .Wild type and mutated pendrin allelic variants were functionally characterized in a heterologous over-expression system . The Cl (-)/I (-) and Cl (-)/OH (-) exchange activities were assessed by fluorometric methods suitable for measuring iodide fluxes and the intracellular pH .Both the Cl (-)/I (-) and the Cl (-)/OH (-) exchange activities of pendrin V 239 D , G 334 V X 335 and I 487 Y FSX 39 were significantly reduced with respect to the wild type , with V 239 D displaying a residual iodide transport .Functional assays confirmed the diagnosis of non-syndromic EVA due to SLC 26 A 4 mutations performed by radiological and molecular tests in deaf patients belonging to the Israeli Jewish and Palestinian Arab populations . The new finding that the V 239 D mutation displays residual function suggests that the symptoms caused by this mutation could be ameliorated by a pendrin 'activator ', if available .

Diseases
Validation

Diseases presenting "hearing loss" symptom

22q11.2 deletion syndrome

achondroplasia

adrenomyeloneuropathy

alexander disease

benign recurrent intrahepatic cholestasis

canavan disease

cohen syndrome

congenital toxoplasmosis

dentinogenesis imperfecta

fabry disease

familial mediterranean fever

heparin-induced thrombocytopenia

hirschsprung disease

holt-oram syndrome

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

kabuki syndrome

kallmann syndrome

neonatal adrenoleukodystrophy

pendred syndrome

von hippel-lindau disease

wolf-hirschhorn syndrome

This symptom has already been validated