Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss

Pu Dai, Andrew K. Stewart, Fouad Chebib, Ann Hsu, Julia Rozenfeld, Deliang Huang, Dongyang Kang, Va Lip, Hong Fang, Hong Shao, Xin Liu, Fei Yu, Huijun Yuan, Margaret Kenna, David T. Miller, Yiping Shen, Weiyan Yang, Israel Zelikovic, Orah S. Platt, Dongyi HanSeth L. Alper, Bai Lin Wu

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Mutations of the human SLC26A4/PDS gene constitute the most common cause of syndromic and nonsyndromic hearing loss. Definition of the SLC26A4 mutation spectrum among different populations with sensorineural hearing loss is important for development of optimal genetic screening services for congenital hearing impairment. We screened for SLC26A4 mutations among Chinese and U.S. subjects with hearing loss, using denaturing HPLC (DHPLC) and direct DNA sequencing. Fifty-two of 55 Chinese subjects with deafness accompanied by enlargement of the vestibular aqueduct (EVA) exhibited at least one mutant SLC26A4 allele, whereas SLC26A4 mutations were found in only 2 of 116 deaf Chinese patients without EVA. The spectrum of SLC26A4 mutations differed among Chinese and U.S. subjects and included 10 previously unreported SLC26A4 variants: 4 in the Chinese population (p.E303Q, p.X329, p.X467, p.X573) and 6 in the U.S. population (p.V250A, p.D266N, p.F354S, p.D697A, p.K715N, p.E737D). Among the seven novel inframe missense mutations, five encoded SLC26A4 proteins with substantially reduced Cl-/anion exchange activity as expressed and measured in Xenopus oocytes, but four of these were sufficiently active to allow study of anion selectivity. The only mutant polypeptide exhibiting complete loss of anion exchange function, p.E303Q, was expressed at or near the oocyte surface at near-wild-type levels. Two variants, p.F354S and p.E737D, displayed selective reduction in relative rate of Cl-/HCO 3- exchange compared with similarly measured rates of Cl-/Cl- and Cl-/I- exchange. Our data show that mutation analysis of the SLC26A4 gene is of high diagnostic yield among subjects with deafness and bilateral EVA in both China and the U.S. However, the pathogenicity of monoallelic SLC26A4 gene variants in patients with hearing loss remains unclear in many instances.

Original languageEnglish (US)
Pages (from-to)281-290
Number of pages10
JournalPhysiological Genomics
Volume38
Issue number3
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

Fingerprint

Vestibular Aqueduct
Mutation
Hearing Loss
Anions
Deafness
Oocytes
Genetic Services
Population
Genes
Sensorineural Hearing Loss
Genetic Testing
Missense Mutation
Xenopus
DNA Sequence Analysis
Virulence
Nonsyndromic Deafness
China
Alleles
High Pressure Liquid Chromatography
Peptides

Keywords

  • Chloride/bicarbonate exchange
  • Enlargement of vestibular aqueduct
  • Goiter
  • Iodide transport
  • Pendred syndrome

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss. / Dai, Pu; Stewart, Andrew K.; Chebib, Fouad; Hsu, Ann; Rozenfeld, Julia; Huang, Deliang; Kang, Dongyang; Lip, Va; Fang, Hong; Shao, Hong; Liu, Xin; Yu, Fei; Yuan, Huijun; Kenna, Margaret; Miller, David T.; Shen, Yiping; Yang, Weiyan; Zelikovic, Israel; Platt, Orah S.; Han, Dongyi; Alper, Seth L.; Wu, Bai Lin.

In: Physiological Genomics, Vol. 38, No. 3, 01.01.2009, p. 281-290.

Research output: Contribution to journalArticle

Dai, P, Stewart, AK, Chebib, F, Hsu, A, Rozenfeld, J, Huang, D, Kang, D, Lip, V, Fang, H, Shao, H, Liu, X, Yu, F, Yuan, H, Kenna, M, Miller, DT, Shen, Y, Yang, W, Zelikovic, I, Platt, OS, Han, D, Alper, SL & Wu, BL 2009, 'Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss', Physiological Genomics, vol. 38, no. 3, pp. 281-290. https://doi.org/10.1152/physiolgenomics.00047.2009
Dai, Pu ; Stewart, Andrew K. ; Chebib, Fouad ; Hsu, Ann ; Rozenfeld, Julia ; Huang, Deliang ; Kang, Dongyang ; Lip, Va ; Fang, Hong ; Shao, Hong ; Liu, Xin ; Yu, Fei ; Yuan, Huijun ; Kenna, Margaret ; Miller, David T. ; Shen, Yiping ; Yang, Weiyan ; Zelikovic, Israel ; Platt, Orah S. ; Han, Dongyi ; Alper, Seth L. ; Wu, Bai Lin. / Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss. In: Physiological Genomics. 2009 ; Vol. 38, No. 3. pp. 281-290.
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