Trends in Endocrinology & Metabolism
ReviewPendred syndrome and iodide transport in the thyroid
Section snippets
Pendred syndrome
The association of familial deafness and nonendemic goiter (see Glossary) was first described by Vaughan Pendred in 1896 [1]. Pendred syndrome (OMIM 274600) is an autosomal recessive disorder defined by sensorineural hearing impairment, goiter, and a partial defect in iodide organification 2, 3, 4, 5, 6. Pendred syndrome is thought to account for ∼10% of all cases of syndromic deafness 7, 8.
The clinical hallmark of Pendred syndrome is sensorineural hearing impairment. The majority of patients
Molecular basis of Pendred syndrome, the SLC26A4 gene and pendrin
Pendred syndrome and familial EVA with a positive perchlorate test result are caused by homozygous or compound heterozygous mutations in the SLC26A4 gene, which encodes pendrin [5]. The SLC26A4 gene is located on chromosome 7q22–31.1 in close vicinity to the SLC26A2 and SLC26A5 genes. This colocalization and the highly similar gene structure of these three genes suggest that they have evolved from a common ancestor [5]. The SLC26A4 gene, originally referred to as PDS gene, consists of 21 exons
Role of pendrin in the inner ear
In the developing wild-type mouse, in situ hybridization has detected Slc26a4 mRNA predominantly in the endolymphatic duct and sac, in areas of the utricule and saccule (see Glossary), and in the external cochlear sulcus region [44]. This expression pattern involves regions that are important for endolymphatic fluid resorption. Phenotypic characterization of Slc26a4-knockout mice has provided a more detailed understanding of the role of pendrin in the inner ear [45]. The knockout mice are deaf,
Role of pendrin in the thyroid
The thyroid follicle forms the functional unit of the thyroid and is essential for normal synthesis of thyroid hormone [21]. At the basolateral membrane of thyroid follicular cells, iodide is actively transported into thyroid follicular cells by the sodium-iodide symporter (NIS/SLC5A5) [49], in a process that is dependent on the sodium gradient generated by the Na/K-ATPase (Figure 2) [50]. At the apical membrane, iodide is released into the follicular lumen where it is oxidized by
Pendrin in the kidney
SLC26A4 mRNA expression was found to be abundant in the kidney, in particular in the renal cortex 5, 31. Reverse-transcription polymerase chain reaction performed with RNA from specific nephron segments led to the detection of SLC26A4 expression in the cortical collecting duct [31]. Immunohistochemical and immunoblot studies localized pendrin at the apical brush-border membrane in type B and in non-A/non-B intercalated cells 31, 32. Type B intercalated cells are involved in the secretion of
Pendrin in other tissues
Pendrin expression has been reported in several other tissues. Immunohistochemical studies suggest that the NIS protein is present on the entire membrane of the cytotrophoblast in the placenta, and that pendrin is located at the brush border membrane of syncytiotrophoblast cells facing the maternal side [54]. Further studies addressing the functional significance of NIS and pendrin in the placenta are not currently available.
Iodide is secreted into the milk and the concentrations are
Summary and perspective
Pendred syndrome and familial EVA with a positive perchlorate test are caused by biallelic mutations in the anion transporter SLC26A4 gene, which encodes pendrin. The phenotypic characterization of the Slc26a4 knockout mouse revealed that pendrin is essential for anion and fluid transport and for maintenance of the endocochlear potential. In the absence of pendrin, the endolymphatic system undergoes a progressive enlargement that results in severe degeneration of sensory cells and otoconia (see
Acknowledgements
This work has been supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (1R01 DK63024–01 to P.K.), and a 2007 Endocrine Fellows Foundation Grant “Regulation of Pendrin by Thyrotropin in Thyroid Cells” (to L.P.).
Glossary
- Allelic heterogeneity
- Different mutations in the same gene or genetic locus resulting in an identical or similar phenotype.
- CFTR
- Cystic fibrosis conductance regulator.
- CHO cells
- Chinese hamster ovary cells.
- COS-7 cells
- Green monkey kidney cells.
- DEHAL1
- Iodotyrosine dehalogenase 1.
- DOCP
- Deoxycorticosterone pivalate (an aldosterone antagonist).
- DUOX2
- Dual oxidase 2.
- Enlarged vestibular aqueduct
- A vestibular aqueduct is considered enlarged if it is greater than 1.5 mm. If it is enlarged, the endolymphatic duct
References (81)
Deaf-mutism and goitre
Lancet
(1896)- et al.
Association of congenital deafness with goitre: the nature of the thyroid defect
Lancet
(1958) Radiological malformations of the ear in Pendred syndrome
Clin. Radiol.
(1998)Functional characterization of pendrin in a polarized cell system: evidence for pendrin-mediated apical iodide efflux
J. Biol. Chem.
(2004)Effects of thyroglobulin and pendrin on iodide flux through the thyrocyte
Trends Endocrinol. Metab.
(2001)The syndrome of sporadic goitre and congenital deafness
Q. J. Med.
(1960)- et al.
Pendred's syndrome: association of congenital deafness with sporadic goiter
Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS)
Nat. Genet.
(1997)Pendred's syndrome: clinical characteristics and molecular basis
Curr. Opin. Endocrinol. Diabetes
(1999)Pendred syndrome: 100 years of underascertainement
Q. J. Med.
(1997)
Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations
Hum. Mutat.
Progressive sensorineural hearing loss and a widened vestibular aqueduct in Pendred syndrome
Arch. Otolaryngol. Head Neck Surg.
Molecular analysis of the Pendred's syndrome gene and magnetic resonance imaging studies of the inner ear are essential for the diagnosis of true Pendred's syndrome
J. Clin. Endocrinol. Metab.
SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities
J. Med. Genet.
The anatomical section of a boy born deaf (Mondini translation)
Am. J. Otol.
Non-endemic goitre and deafness
Acta Paediatr.
Association of congenital deafness with goitre (Pendred's syndrome)
Ann. Hum. Genet.
Pendred syndrome: evidence for genetic homogeneity and further refinement of linkage
J. Med. Genet.
Phenotypes associated with replacement of His by Arg in the Pendred syndrome gene
Eur. J. Endocrinol.
Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations
Hum. Genet.
Evaluation and limitations of the perchlorate test in the study of thyroid function
J. Clin. Endocrinol. Metab.
Thyroid hormone synthesis: thyroid iodine metabolism
The association of deafness with thyroid dysfunction
Br. Med. Bull.
Phenocopies for deafness and goiter development in a large inbred kindred with Pendred's syndrome caused by a novel mutation in the PDS gene
J. Clin. Endocrinol. Metab.
Clinical and molecular analysis of three Mexican families with Pendred's syndrome
Eur. J. Endocrinol.
A family of mammalian anion transporters and their involvement in human genetic diseases
Hum. Mol. Genet.
The SLC26 gene family of multifunctional anion exchangers
Pflugers Arch.
Pathogenetics of the human SLC26 transporters
Curr. Med. Chem.
Prestin is the motor protein of cochlear outer hair cells
Nature
Intracellular anions as the voltage sensor of prestin, the outer hair cell motor protein
Science
The Pendred syndrome gene encodes a chloride-iodide transport protein
Nat. Genet.
Pendrin: an apical Cl−/OH−/HCO3− exchanger in the kidney cortex
Am. J. Physiol. Renal Physiol.
Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion
Proc. Natl. Acad. Sci. U. S. A.
Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells
J. Clin. Endocrinol. Metab.
Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome
J. Clin. Endocrinol. Metab.
Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells
Endocrinology
The STAS domain - a link between anion transporters and antisigma-factor antagonists
Curr. Biol.
A molecular mechanism for aberrant CFTR-dependent HCO(3)(−) transport in cystic fibrosis
EMBO J.
Gating of CFTR by the STAS domain of SLC26 transporters
Nat. Cell Biol.
Regulatory interaction between CFTR and the SLC26 transporters
Novartis Found. Symp.
Cited by (95)
Disorders of the Thyroid Gland
2023, Avery's Diseases of the NewbornEffects of salicylate derivatives on localization of p.H723R allele product of SLC26A4
2022, Auris Nasus LarynxMechanisms of action of agrochemicals acting as endocrine disrupting chemicals
2020, Molecular and Cellular EndocrinologyDisorders of the Thyroid Gland
2018, Avery's Diseases of the Newborn: Tenth EditionAn update of common autosomal recessive non-syndromic hearing loss genes in Iranian population
2017, International Journal of Pediatric OtorhinolaryngologyCitation Excerpt :In studies on Iranian populations, a nonsense c.1543delA mutation in exon 6 of this gene which cause premature stop codon has been reported [16]. SLC26A4 gene encodes pendrin protein which acts as an anion transporter and also a microtubule associated structural protein that is likely involved in regulation of endolymphatic fluid pH through secretion of HCO3− ion [40]. Up to now, over 150 SLC26A4 mutations have been reported in patients which associated with NSHL and Pendred syndrome (PDS).
Defects of Thyroid Hormone Synthesis and Action
2017, Endocrinology and Metabolism Clinics of North America