Skip to main content
SpringerLink
Log in

Atrophic thyroid follicles and inner ear defects reminiscent of cochlear hypothyroidism in Slc26a4-related deafness

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Thyroid hormone is essential for inner ear development and is required for auditory system maturation. Human mutations in SLC26A4 lead to a syndromic form of deafness with enlargement of the thyroid gland (Pendred syndrome) and non-syndromic deafness (DFNB4). We describe mice with an Slc26a4 mutation, Slc26a4 loop/loop, which are profoundly deaf but show a normal sized thyroid gland, mimicking non-syndromic clinical signs. Histological analysis of the thyroid gland revealed defective morphology, with a majority of atrophic microfollicles, while measurable thyroid hormone in blood serum was within the normal range. Characterization of the inner ear showed a spectrum of morphological and molecular defects consistent with inner ear pathology, as seen in hypothyroidism or disrupted thyroid hormone action. The pathological inner ear hallmarks included thicker tectorial membrane with reduced β-tectorin protein expression, the absence of BK channel expression of inner hair cells, and reduced inner ear bone calcification. Our study demonstrates that deafness in Slc26a4 loop/loop mice correlates with thyroid pathology, postulating that sub-clinical thyroid morphological defects may be present in some DFNB4 individuals with a normal sized thyroid gland. We propose that insufficient availability of thyroid hormone during inner ear development plays an important role in the mechanism underlying deafness as a result of SLC26A4 mutations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Albert S, Blons H et al (2006) SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations. Eur J Hum Genet 14(6):773–779

    Article  CAS  PubMed  Google Scholar 

  • Arvan P, Di Jeso B (2005) Thyroglobulin structure, function, and biosynthesis. In: Braverman L, Utiger R (eds) Werner and Ingbar’s The thyroid: a fundamental and clinical text. Lippincott Williams & Wilkins, New York, pp 77–95

    Google Scholar 

  • Bizhanova A, Kopp P (2011) Controversies concerning the role of pendrin as an apical iodide transporter in thyroid follicular cells. Cell Physiol Biochem 28(3):485–490

    Article  CAS  PubMed  Google Scholar 

  • Bizhanova A, Chew TL et al (2011) Analysis of cellular localization and function of carboxy-terminal mutants of pendrin. Cell Physiol Biochem 28(3):423–434

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bradley DJ, Towle HC et al (1994) α and β thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform-specific transcriptional regulation in vivo. Proc Natl Acad Sci USA 91(2):439–443

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brandt N, Kuhn S et al (2007) Thyroid hormone deficiency affects postnatal spiking activity and expression of Ca2+ and K+ channels in rodent inner hair cells. J Neurosci 27(12):3174–3186

    Article  CAS  PubMed  Google Scholar 

  • Brownstein ZN, Dror AA et al (2008) A novel SLC26A4 (PDS) deafness mutation retained in the endoplasmic reticulum. Arch Otolaryngol Head Neck Surg 134(4):403–407

    Google Scholar 

  • Christ S, Biebel UW et al (2004) Hearing loss in athyroid pax8 knockout mice and effects of thyroxine substitution. Audiol Neurootol 9(2):88–106

    Article  CAS  PubMed  Google Scholar 

  • DeLong GR, Stanbury JB et al (1985) Neurological signs in congenital iodine-deficiency disorder (endemic cretinism). Dev Med Child Neurol 27(3):317–324

    Article  CAS  PubMed  Google Scholar 

  • Dohan O, De la Vieja A et al (2003) The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev 24(1):48–77

    Article  CAS  PubMed  Google Scholar 

  • Dorwart MR, Shcheynikov N et al (2008) The solute carrier 26 family of proteins in epithelial ion transport. Physiology (Bethesda) 23:104–114

    Article  CAS  Google Scholar 

  • Dror AA, Politi Y et al (2010) Calcium oxalate stone formation in the inner ear as a result of an Slc26a4 mutation. J Biol Chem 285(28):21724–21735

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dror AA, Brownstein Z et al (2011) Integration of human and mouse genetics reveals pendrin function in hearing and deafness. Cell Physiol Biochem 28(3):535–544

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Everett LA, Glaser B et al (1997) Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 17(4):411–422

    Article  CAS  PubMed  Google Scholar 

  • Everett LA, Belyantseva IA et al (2001) Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. Hum Mol Genet 10(2):153–161

    Article  CAS  PubMed  Google Scholar 

  • Fang Q, Giordimaina AM et al (2012) Genetic background of Prop1 df mutants provides remarkable protection against hypothyroidism-induced hearing impairment. J Assoc Res Otolaryngol 13(2):173–184

    Article  PubMed Central  PubMed  Google Scholar 

  • Ferrer-Costa C, Orozco M et al (2002) Characterization of disease-associated single amino acid polymorphisms in terms of sequence and structure properties. J Mol Biol 315(4):771–786

    Article  CAS  PubMed  Google Scholar 

  • Forrest D, Erway LC et al (1996) Thyroid hormone receptor beta is essential for development of auditory function. Nat Genet 13(3):354–357

    Article  CAS  PubMed  Google Scholar 

  • Fraser GR (1965) Association of congenital deafness with goitre (Pendred’s syndrome): a study of 207 families. Ann Hum Genet 28:201–249

    Article  CAS  PubMed  Google Scholar 

  • Frische S, Kwon TH et al (2003) Regulated expression of pendrin in rat kidney in response to chronic NH4Cl or NaHCO3 loading. Am J Physiol Ren Physiol 284(3):F584–F593

    CAS  Google Scholar 

  • Gillam MP, Sidhaye AR et al (2004) Functional characterization of pendrin in a polarized cell system. Evidence for pendrin-mediated apical iodide efflux. J Biol Chem 279(13):13004–13010

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez Trevino O, Karamanoglu Arseven O et al (2001) Clinical and molecular analysis of three Mexican families with Pendred’s syndrome. Eur J Endocrinol 144(6):585–593

    Article  CAS  PubMed  Google Scholar 

  • Hrabe de Angelis MH, Flaswinkel H et al (2000) Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nat Genet 25(4):444–447

    Article  CAS  PubMed  Google Scholar 

  • Kim HM, Wangemann P (2010) Failure of fluid absorption in the endolymphatic sac initiates cochlear enlargement that leads to deafness in mice lacking pendrin expression. PLoS One 5(11):e14041

    Article  PubMed Central  PubMed  Google Scholar 

  • Kim HM, Wangemann P (2011) Epithelial cell stretching and luminal acidification lead to a retarded development of stria vascularis and deafness in mice lacking pendrin. PLoS One 6(3):e17949

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Knipper M, Gestwa L et al (1999) Distinct thyroid hormone-dependent expression of TrKB and p75NGFR in nonneuronal cells during the critical TH-dependent period of the cochlea. J Neurobiol 38(3):338–356

    Article  CAS  PubMed  Google Scholar 

  • Knipper M, Richardson G et al (2001) Thyroid hormone-deficient period prior to the onset of hearing is associated with reduced levels of beta-tectorin protein in the tectorial membrane: implication for hearing loss. J Biol Chem 276(42):39046–39052

    Article  CAS  PubMed  Google Scholar 

  • Kopp P (2005) Thyroid hormone synthesis: thyroid iodine metabolism. In: Braverman L, Utiger R (eds) Werner and Ingbar’s The thyroid: a fundamental and clinical text. Lippincott Williams & Wilkins, New York, pp 52–76

    Google Scholar 

  • Lacroix L, Mian C et al (2001) Na+/I− symporter and Pendred syndrome gene and protein expressions in human extra-thyroidal tissues. Eur J Endocrinol 144(3):297–302

    Article  CAS  PubMed  Google Scholar 

  • Laurila K, Vihinen M (2009) Prediction of disease-related mutations affecting protein localization. BMC Genom 10:122

    Article  Google Scholar 

  • Lu YC, Wu CC et al (2011) Establishment of a knock-in mouse model with the SLC26A4 c.919-2A>G mutation and characterization of its pathology. PLoS One 6(7):e22150

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mansouri A, Chowdhury K et al (1998) Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet 19(1):87–90

    Article  CAS  PubMed  Google Scholar 

  • Morgans ME, Trotter WR (1958) Association of congenital deafness with goitre; the nature of the thyroid defect. Lancet 1(7021):607–609

    Article  CAS  PubMed  Google Scholar 

  • Ng L, Goodyear RJ et al (2004) Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase. Proc Natl Acad Sci USA 101(10):3474–3479

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Park HJ, Lee SJ et al (2005) Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans. Clin Genet 67(2):160–165

    Article  PubMed  Google Scholar 

  • Pera A, Dossena S et al (2008) Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA. Proc Natl Acad Sci USA 105(47):18608–18613

    Google Scholar 

  • Pesce L, Bizhanova A et al (2012) TSH regulates pendrin membrane abundance and enhances iodide efflux in thyroid cells. Endocrinology 153(1):512–521

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pryor SP, Madeo AC et al (2005) 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 42(2):159–165

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Refetoff S, DeWind LT et al (1967) Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 27(2):279–294

    Article  CAS  PubMed  Google Scholar 

  • Richardson GP, Lukashkin AN et al (2008) The tectorial membrane: one slice of a complex cochlear sandwich. Curr Opin Otolaryngol Head Neck Surg 16(5):458–464

    Article  PubMed Central  PubMed  Google Scholar 

  • Rovet J, Walker W et al (1996) Long-term sequelae of hearing impairment in congenital hypothyroidism. J Pediatr 128(6):776–783

    Article  CAS  PubMed  Google Scholar 

  • Royaux IE, Suzuki K et al (2000) 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 141(2):839–845

    Article  CAS  PubMed  Google Scholar 

  • Royaux IE, Wall SM et al (2001) Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion. Proc Natl Acad Sci USA 98(7):4221–4226

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rusch A, Ng L et al (2001) Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors. J Neurosci 21(24):9792–9800

    CAS  PubMed  Google Scholar 

  • Sato E, Nakashima T et al (2001) Phenotypes associated with replacement of His723 by Arg in the Pendred syndrome gene. Eur J Endocrinol 145(6):697–703

    Article  CAS  PubMed  Google Scholar 

  • Scott DA, Wang R et al (1999) The Pendred syndrome gene encodes a chloride–iodide transport protein. Nat Genet 21(4):440–443

    Article  CAS  PubMed  Google Scholar 

  • Senou M, Khalifa C et al (2010) A coherent organization of differentiation proteins is required to maintain an appropriate thyroid function in the Pendred thyroid. J Clin Endocrinol Metab 95(8):4021–4030

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Royaux IE et al (2002) Expression of PDS/Pds, the Pendred syndrome gene, in endometrium. J Clin Endocrinol Metab 87(2):938

    Article  CAS  PubMed  Google Scholar 

  • Tsukamoto K, Suzuki H et al (2003) Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese. Eur J Hum Genet 11(12):916–922

    Article  CAS  PubMed  Google Scholar 

  • van den Hove MF, Croizet-Berger K et al (2006) The loss of the chloride channel, ClC-5, delays apical iodide efflux and induces a euthyroid goiter in the mouse thyroid gland. Endocrinology 147(3):1287–1296

    Article  PubMed  Google Scholar 

  • Wangemann P, Nakaya K et al (2007) Loss of cochlear HCO3 − secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model. Am J Physiol Ren Physiol 292(5):F1345–F1353

    Article  CAS  Google Scholar 

  • Wangemann P, Kim HM et al (2009) Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression. Am J Physiol Ren Physiol 297(5):F1435–F1447

    Article  CAS  Google Scholar 

  • Winter H, Braig C et al (2006) Thyroid hormone receptors TRα1 and TRβ differentially regulate gene expression of Kcnq4 and prestin during final differentiation of outer hair cells. J Cell Sci 119(Pt 14):2975–2984

    Article  CAS  PubMed  Google Scholar 

  • Yoon JS, Park HJ et al (2008) Heterogeneity in the processing defect of SLC26A4 mutants. J Med Genet 45(7):411–419

    Article  CAS  PubMed  Google Scholar 

  • Yoshida A, Taniguchi S et al (2002) Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells. J Clin Endocrinol Metab 87(7):3356–3361

    Article  CAS  PubMed  Google Scholar 

  • Zwaenepoel I, Mustapha M et al (2002) Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22. Proc Natl Acad Sci USA 99(9):6240–6245

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Leonid Mittelman for training in confocal microscopy, Vered Holdengreber for SEM advice and support; Jørgen Frøkiær, Christine Petit, Guy Richardson, and Tobias Moser for providing antibodies. This work was supported by the National Institutes of Health (NIDCD) R01DC011835 and I-CORE Gene Regulation in Complex Human Disease, Center No. 41/11.

Author information

Authors and Affiliations

  1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 69978, Israel

    Amiel A. Dror, Danielle R. Lenz, Shaked Shivatzki, Keren Cohen, Osnat Ashur-Fabian & Karen B. Avraham

  2. Translational Hemato-Oncology, Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, 44299, Israel

    Keren Cohen & Osnat Ashur-Fabian

Authors
  1. Amiel A. Dror
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danielle R. Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shaked Shivatzki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keren Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Osnat Ashur-Fabian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karen B. Avraham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karen B. Avraham.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dror, A.A., Lenz, D.R., Shivatzki, S. et al. Atrophic thyroid follicles and inner ear defects reminiscent of cochlear hypothyroidism in Slc26a4-related deafness. Mamm Genome 25, 304–316 (2014). https://doi.org/10.1007/s00335-014-9515-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-014-9515-1

Keywords

Search

Navigation