Review
Pendred syndrome and iodide transport in the thyroid

https://doi.org/10.1016/j.tem.2008.07.001Get rights and content

Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing impairment, presence of goiter, and a partial defect in iodide organification, which may be associated with insufficient thyroid hormone synthesis. Goiter development and development of hypothyroidism are variable and depend on nutritional iodide intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4 gene, which encodes pendrin, a transporter of chloride, bicarbonate and iodide. This review discusses the controversies surrounding the potential role of pendrin in mediating apical iodide efflux into the lumen of thyroid follicles, and discusses its functional role in the kidney and the inner ear.

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)

  • C. Campbell

    Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations

    Hum. Mutat.

    (2001)
  • C.W.R.J. Cremers

    Progressive sensorineural hearing loss and a widened vestibular aqueduct in Pendred syndrome

    Arch. Otolaryngol. Head Neck Surg.

    (1998)
  • L. Fugazzola

    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.

    (2000)
  • S.P. Pryor

    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.

    (2005)
  • G.J. Hartley et al.

    The anatomical section of a boy born deaf (Mondini translation)

    Am. J. Otol.

    (1997)
  • L.R. Nilsson

    Non-endemic goitre and deafness

    Acta Paediatr.

    (1964)
  • G.R. Fraser

    Association of congenital deafness with goitre (Pendred's syndrome)

    Ann. Hum. Genet.

    (1965)
  • E. Gausden

    Pendred syndrome: evidence for genetic homogeneity and further refinement of linkage

    J. Med. Genet.

    (1997)
  • E. Sato

    Phenotypes associated with replacement of His by Arg in the Pendred syndrome gene

    Eur. J. Endocrinol.

    (2001)
  • S. Usami

    Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations

    Hum. Genet.

    (1999)
  • L. Baschieri

    Evaluation and limitations of the perchlorate test in the study of thyroid function

    J. Clin. Endocrinol. Metab.

    (1963)
  • P. Kopp

    Thyroid hormone synthesis: thyroid iodine metabolism

  • W.R. Trotter

    The association of deafness with thyroid dysfunction

    Br. Med. Bull.

    (1960)
  • P. Kopp

    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.

    (1999)
  • O. Gonzalez Trevino

    Clinical and molecular analysis of three Mexican families with Pendred's syndrome

    Eur. J. Endocrinol.

    (2001)
  • L.A. Everett et al.

    A family of mammalian anion transporters and their involvement in human genetic diseases

    Hum. Mol. Genet.

    (1999)
  • D.B. Mount et al.

    The SLC26 gene family of multifunctional anion exchangers

    Pflugers Arch.

    (2004)
  • P.A. Dawson et al.

    Pathogenetics of the human SLC26 transporters

    Curr. Med. Chem.

    (2005)
  • J. Zheng

    Prestin is the motor protein of cochlear outer hair cells

    Nature

    (2000)
  • D. Oliver

    Intracellular anions as the voltage sensor of prestin, the outer hair cell motor protein

    Science

    (2001)
  • D.A. Scott

    The Pendred syndrome gene encodes a chloride-iodide transport protein

    Nat. Genet.

    (1999)
  • M. Soleimani

    Pendrin: an apical Cl/OH/HCO3 exchanger in the kidney cortex

    Am. J. Physiol. Renal Physiol.

    (2001)
  • I.E. Royaux

    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.

    (2001)
  • A. Yoshida

    Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells

    J. Clin. Endocrinol. Metab.

    (2002)
  • J.P. Taylor

    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.

    (2002)
  • I.E. Royaux

    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

    (2000)
  • L. Aravind et al.

    The STAS domain - a link between anion transporters and antisigma-factor antagonists

    Curr. Biol.

    (2001)
  • S.B. Ko

    A molecular mechanism for aberrant CFTR-dependent HCO(3)(−) transport in cystic fibrosis

    EMBO J.

    (2002)
  • S.B. Ko

    Gating of CFTR by the STAS domain of SLC26 transporters

    Nat. Cell Biol.

    (2004)
  • N. Shcheynikov

    Regulatory interaction between CFTR and the SLC26 transporters

    Novartis Found. Symp.

    (2006)
  • Cited by (95)

    • Disorders of the Thyroid Gland

      2023, Avery's Diseases of the Newborn
    • Disorders of the Thyroid Gland

      2018, Avery's Diseases of the Newborn: Tenth Edition
    • An update of common autosomal recessive non-syndromic hearing loss genes in Iranian population

      2017, International Journal of Pediatric Otorhinolaryngology
      Citation 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
    View all citing articles on Scopus
    View full text