Pendrin function and regulation in Xenopus oocytes.

[pendred syndrome]

SLC 26 A 4 /PDS mutations cause Pendred Syndrome and non-syndromic deafness . but some aspects of function and regulation of the SLC 26 A 4 polypeptide gene product , pendrin , remain controversial or incompletely understood . We have therefore extended the functional analysis of wildtype and mutant pendrin in Xenopus oocytes , with studies of isotopic flux , electrophysiology , and protein localization . Pendrin mediated electroneutral , pH-insensitive , DIDS-insensitive anion exchange , with extracellular K ((1 /2 )) (in mM ) of 1 .9 (Cl (-)), 1 .8 (I (-)), and 0 .9 (Br (-)). The unusual phenotype of Pendred Syndrome mutation E 303 Q (loss -of-function with normal surface expression ) prompted systematic mutagenesis at position 303 . Only mutant E 303 K exhibited loss -of-function unrescued by forced overexpression . Mutant E 303 C was insensitive to charge modification by methanethiosulfonates . The corresponding mutants SLC 26 A 2 E 336 Q , SLC 26 A 3 E 293 Q , and SLC 26 A 6 E 298 Q exhibited similar loss -of-function phenotypes , with wildtype surface expression also documented for SLC 26 A 2 E 336 Q . The strong inhibition of wildtype SLC 26 A 2 , SLC 26 A 3 , and SLC 26 A 6 by phorbol ester contrasts with its modest inhibition of pendrin . Phorbol ester inhibition of SLC 26 A 2 , SLC 26 A 3 , and SLC 26 A 6 was blocked by coexpressed kinase-dead PKC Î´ but was without effect on pendrin . Mutation of SLC 26 A 2 serine residues conserved in PKC Î´ -sensitive SLC 26 proteins but absent from pendrin failed to reduce PKC Î´ sensitivity of SLC 26 A 2 (190 ).

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