Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4)

• Published in: Human molecular genetics 2000-07, Vol.9 (11), p.1709-1715
• Main Authors: SCOTT, D. A, RONG WANG, KREMAN, T. M, ANDREWS, M, MCDONALD, J. M, BISHOP, J. R, SMITH, R. J. H, KARNISKI, L. P, SHEFFIELD, V. C
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Substitution; Animals; Biological and medical sciences; Carrier Proteins - genetics; chloride; chromosome 7; DFNB4 gene; Endocrinopathies; Female; Genetic Variation; Goiter - genetics; Goiter - pathology; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - pathology; Humans; iodide; Iodine - pharmacokinetics; Medical sciences; Membrane Transport Proteins; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Oocytes - cytology; Oocytes - metabolism; PDS gene; Pendred syndrome; pendrin protein; Phenotype; RNA, Complementary - administration & dosage; Sulfate Transporters; Thyroid. Thyroid axis (diseases); Xenopus laevis
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.11.1709

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.