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Journal of Endocrinological Investigation

, Volume 27, Issue 5, pp 430–435 | Cite as

Mutations in the SLC26A4 (pendrin) gene in patients with sensorineural deafness and enlarged vestibular aqueduct

  • F. BogazziEmail author
  • D. Russo
  • F. Raggi
  • F. Ultimieri
  • S. Berrettini
  • F. Forli
  • L. Grasso
  • C. Ceccarelli
  • S. Mariotti
  • A. Pinchera
  • L. Bartalena
  • E. Martino
Original Article

Abstract

Pendred syndrome and the enlarged vestibular aqueduct (EVA) are considered phenotypic variations of the same entity due to mutations in the SLC26A4 (pendrin) gene. Pendred syndrome consists in sensorineural deafness, goiter and impaired thyroid hormone synthesis while in EVA thyroid function seems to be preserved. The aim of this study was to evaluate thyroid function and morphology and to look for mutations in the SLC26A4 gene in patients presented with EVA. Among 57 consecutive patients with sensorineural deafness 15 with EVA, as assessed by magnetic resonance imaging (MRI), were identified and studied. A complete evaluation of thyroid function including thyroid echography and perchlorate discharge test was carried out in all patients with EVA; all exons of the SLC26A4 gene were amplified from peripheral leukocytes and directly sequenced, using specific intronic primers. Out of 15 patients with EVA, goiter was present in 8 (53%), hypothyroidism in 7 (47%), increased serum thyroglobulin levels in 8 (53%) and a positive perchlorate discharge test in 10 (67%). Nine alleles of the SLC26A4 gene were mutated: 2 novel mutations (L465W and G497R) and 4 already known mutations (T410M, R409H, T505N and IVS1001+1G>A) were found. Four subjects were compound heterozygous and 1 heterozygous (G497R/wt). All patients harbouring mutations in the SLC26A4 gene had goiter and a positive perchlorate discharge test: 3 were slightly hypothyroid and 2 euthyroid. The remaining 10 patients had no mutations in the SLC26A4 gene: 4 of them were hypothyroid, 2 with goiter and positive perchlorate discharge test, 2 without goiter and with negative perchlorate discharge test. Two patients without mutations were euthyroid with positive perchlorate discharge test. Patients with mutations in the SLC26A4 gene had larger thyroid volume (p<0.002), higher serum thyroglobulin (Tg) levels (p<0.002) and greater radioiodine discharge after perchlorate (p=0.09) than patients without mutations. The results of the present study lend support to the concept that all patients with mutated SLC26A4 gene have abnormalities of thyroid function tests.

Key-words

Pendred’s syndrome deafness thyroid hormone synthesis SLC26A4 pendrin 

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References

  1. 1.
    Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997, 17: 411–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Coyle B, Reardon W, Herbrick JA, et al. Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre). Hum Mol Genet 1998, 7: 1105–12.PubMedCrossRefGoogle Scholar
  3. 3.
    Van Hauwe P, Everett LA, Coucke P, et al. Two frequent mis-sense mutations in Pendred syndrome. Hum Mol Genet 1998, 7: 1099–104.PubMedCrossRefGoogle Scholar
  4. 4.
    Bogazzi F, Raggi F, Ultimieri F, et al. A novel mutation in the pendrin gene associated with Pendred’s syndrome. Clin Endocrinol (Oxf) 2000, 52: 279–85.CrossRefGoogle Scholar
  5. 5.
    Gonzalez Trevino O, Karamanoglu Arseven O, Ceballos CJ, et al. Clinical and molecular analysis of three Mexican families with Pendred’s syndrome. Eur J Endocrinol 2001, 144: 585–93.PubMedCrossRefGoogle Scholar
  6. 6.
    Fugazzola L, Cerutti N, Mannavola D, et al. Differential diagnosis between pendred and pseudo-Pendred syndromes: clinical, radiologic, and molecular studies. Pediatr Res 2002, 51: 479–84.PubMedCrossRefGoogle Scholar
  7. 7.
    Lopez-Bigas N, Melchionda S, de Cid R, et al. Erratum: Identification of five new mutations of PDS/SLC26A4 in Mediterranean families with hearing impairment. Hum Mutat 2002, 20: 77–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Park HJ, Shaukat S, Liu XZ, et al. Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness. J Med Genet 2003, 40: 242–8.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Reardon W, OMahoney CF, Trembath R, Jan H, Phelps PD. Enlarged vestibular aqueduct: a radiological marker of Pen-dred syndrome, and mutation of the PDS gene. Q J Med 2000, 93: 99–104.CrossRefGoogle Scholar
  10. 10.
    Phelps PD, Coffey RA, Trembath RC, et al. Radiological malformations of the ear in Pendred syndrome. Clin Radiol 1998, 53: 268–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Campbell C, Cucci RA, Prasad S, et al. Pendred Syndrome, DFNB4, and PDS/SLC26A4 Identification of Eight Novel Mutations and Possible Genotype Correlations. Hum Mutat 2001, 17: 403–11.PubMedCrossRefGoogle Scholar
  12. 12.
    Li XC, Everett LA, Lalwani AK, et al. A mutation in PDS causes non-syndromic recessive deafness. Nat Genet 1998, 18: 215–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Kitamura K, Takahashi k, Nogushi Y, et al. Mutations of Pen-dred syndrome gene (PDS) in patients with large vestibular aqueduct. Acta Otolaryngol 2000, 120: 137–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Scott DA, Wang R, Kreman TM, et al. Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syn-dromic hearing loss (DFNB4). Hum Mol Genet 2000, 9: 1709–15.PubMedCrossRefGoogle Scholar
  15. 15.
    Taylor JP, Metcalfe RA, Watson PF, Weetman AP, Trembath RC. Mutations of the PDS gene, encoding pendrin, are asociated with protein mislocation and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome. J Clin Endocrinol Metab 2002, 87: 1778–84.PubMedCrossRefGoogle Scholar
  16. 16.
    Sato E, Nakashima T, Miura Y, et al. Phenotypes associated with replacement of His by Arg in the Pendred syndrome gene. Eur J Endocrinol 2001, 145: 697–703.PubMedCrossRefGoogle Scholar
  17. 17.
    Bogazzi F, Bartalena L, Martino E. Color flow doppler sonograpphy of the thyroid. In: HJ Baskin ed. Thyroid ultrasound and ultrasound-guided FNAB biopsy. Boston: Kluwer Academic Publishers. 2000, 215–38.CrossRefGoogle Scholar
  18. 18.
    Ausubel FM, Brent R, Kingstone RE, et al. Current protocols in molecular biology. Wiley and Sons, Inc. 1989.Google Scholar
  19. 19.
    Bogazzi F, Bartalena L, Raggi F, Ultimieri F, Martino E. Pendrin does not increase sulfate uptake in mammalian COS-7 cells. J Endocrinol Invest 2000, 23: 170–2.PubMedCrossRefGoogle Scholar
  20. 20.
    Hulander M, Kiernan AE, Blomqvist SR, et al. Lack of pen-drin expression leads to deafness and expansion of the en-dolymphatic compartment in inner ears of Foxi1 null mutant mice. Develompent 2003, 130: 2013–25.Google Scholar
  21. 21.
    Rotman-Pikielny P, Hirschberg K, Maruvada P, et al. Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome. Hum Mol Genet 2002, 11: 2625–33.PubMedCrossRefGoogle Scholar
  22. 22.
    Usami S, Abe S, Weston MD, Shinkawa H, van Camp G, Kimberling WJ. Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations. Hum Genet 1998, 104: 188–92.CrossRefGoogle Scholar
  23. 23.
    Kopp P, Karamanoglu Arseven O, Sabacan L, et al. Phenocopies for deafness and goiter development in a large inbred brazilian kindred with Pendred’s syndrome associated with a novel mutation in the PDS gene. J Clin Endocrinol Metab 1999, 84: 336–41.PubMedGoogle Scholar
  24. 24.
    Everett LA, Belyantseva IA, Noben-Trauth K, et al. Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. Hum Mol Genet 2001, 10: 153–61.PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2004

Authors and Affiliations

  • F. Bogazzi
    • 1
    Email author
  • D. Russo
    • 1
  • F. Raggi
    • 1
  • F. Ultimieri
    • 1
  • S. Berrettini
    • 2
  • F. Forli
    • 2
  • L. Grasso
    • 1
  • C. Ceccarelli
    • 1
  • S. Mariotti
    • 3
  • A. Pinchera
    • 1
  • L. Bartalena
    • 4
  • E. Martino
    • 1
  1. 1.Department of Endocrinology and MetabolismUniversity of PisaPisaItaly
  2. 2.Department of OtolaryngologyUniversity of PisaPisaItaly
  3. 3.Department of EndocrinologyUniversity of CagliariCagliariItaly
  4. 4.Department of EndocrinologyUniversity of InsubriaVareseItaly

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