Regulation of pendrin by pH: dependence on glycosylation.

[pendred syndrome]

Mutations in the anion exchanger pendrin are responsible for Pendred syndrome , an autosomal recessive disease characterized by deafness and goitre . Pendrin is highly expressed in kidney collecting ducts , where it acts as a chloride /bicarbonate exchanger and thereby contributes to the regulation of acid-base homoeostasis and blood pressure . The present study aimed to characterize the intrinsic properties of pendrin . Mouse pendrin was transfected in HEK (human embryonic kidney ) 293 and OKP (opossum kidney proximal tubule ) cells and its activity was determined by monitoring changes in the intracellular pH induced by variations of transmembrane anion gradients . Combining measurements of pendrin activity with mathematical modelling we found that its affinity for Cl-, HCO 3 - and OH - varies with intracellular pH , with increased activity at low intracellular pH . Maximal pendrin activity was also stimulated at low extracellular pH , suggesting the presence of both intracellular and extracellular proton regulatory sites . We identified five putative pendrin glycosylation sites , only two of which are used . Mutagenesis-induced disruption of pendrin glycosylation did not alter its cell-surface expression or polarized targeting to the apical membrane and basal activity , but fully abrogated its sensitivity to extracellular pH . The hither to unknown regulation of pendrin by external pH may constitute a key mechanism in controlling ionic exchanges across the collecting duct and inner ear .

Diseases
Validation

Diseases presenting "deafness" symptom

dentinogenesis imperfecta

epidermolysis bullosa simplex

hirschsprung disease

kabuki syndrome

kallmann syndrome

megacystis-microcolon-intestinal hypoperistalsis syndrome

neonatal adrenoleukodystrophy

oculocutaneous albinism

pendred syndrome

von hippel-lindau disease

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated