Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4).
The PDS gene encodes a transmembrane protein, known as pendrin, which functions as a transporter of iodide and chloride. Mutations in this gene are responsible for Pendred syndrome and autosomal recessive non-syndromic hearing loss at the DFNB4 locus on chromosome 7q31. A screen of 20 individuals from the midwestern USA with non-syndromic hearing loss and dilated vestibular aqueducts identified three people (15%) with PDS mutations. To determine whether PDS mutations in individuals with Pendred syndrome differ functionally from PDS mutations in individuals with non-syndromic hearing loss, we compared three common Pendred syndrome allele variants (L236P, T416P and E384G), with three PDS mutations reported only in individuals with non-syndromic hearing loss (V480D, V653A and I490L/G497S). The mutations associated with Pendred syndrome have complete loss of pendrin-induced chloride and iodide transport, while alleles unique to people with DFNB4 are able to transport both iodide and chloride, albeit at a much lower level than wild-type pendrin. We hypothesize that this residual level of anion transport is sufficient to eliminate or postpone the onset of goiter in individuals with DFNB4. We propose a model for pendrin function in the thyroid in which pendrin transports iodide across the apical membrane of the thyrocyte into the colloid space.
Scott
D A
DA
Howard Hughes Medical Institute and the Department of Pediatrics, University of Iowa Hospitals and Clinics and Iowa City Veterans Affairs, 52242, USA.
Wang
R
R
Kreman
T M
TM
Andrews
M
M
McDonald
J M
JM
Bishop
J R
JR
Smith
R J
RJ
Karniski
L P
LP
Sheffield
V C
VC
D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006042:Goiter / Q000235:genetics* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007455:Iodine / Q000493:pharmacokinetics; D026901:Membrane Transport Proteins; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D018075:RNA, Complementary / Q000008:administration & dosage; D000076988:Sulfate Transporters; D014982:Xenopus laevis
D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D018075:RNA, Complementary; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; D007455:Iodine