TY - JOUR
T1 - Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss
AU - Dai, Pu
AU - Stewart, Andrew K.
AU - Chebib, Fouad
AU - Hsu, Ann
AU - Rozenfeld, Julia
AU - Huang, Deliang
AU - Kang, Dongyang
AU - Lip, Va
AU - Fang, Hong
AU - Shao, Hong
AU - Liu, Xin
AU - Yu, Fei
AU - Yuan, Huijun
AU - Kenna, Margaret
AU - Miller, David T.
AU - Shen, Yiping
AU - Yang, Weiyan
AU - Zelikovic, Israel
AU - Platt, Orah S.
AU - Han, Dongyi
AU - Alper, Seth L.
AU - Wu, Bai Lin
PY - 2009/8
Y1 - 2009/8
N2 - 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.
AB - 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.
KW - Chloride/bicarbonate exchange
KW - Enlargement of vestibular aqueduct
KW - Goiter
KW - Iodide transport
KW - Pendred syndrome
UR - http://www.scopus.com/inward/record.url?scp=68849086394&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68849086394&partnerID=8YFLogxK
U2 - 10.1152/physiolgenomics.00047.2009
DO - 10.1152/physiolgenomics.00047.2009
M3 - Article
C2 - 19509082
AN - SCOPUS:68849086394
SN - 1094-8341
VL - 38
SP - 281
EP - 290
JO - Physiological Genomics
JF - Physiological Genomics
IS - 3
ER -