title: Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss.
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 in-frame 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.
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery and Genetic Testing Center for Deafness, PLA General Hospital, Beijing, People's Republic of China.
authors.forename: Pu
authors.initials: P
authors.lastname: Dai
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Stewart
authors.forename: Fouad
authors.initials: F
authors.lastname: Chebib
authors.forename: Ann
authors.initials: A
authors.lastname: Hsu
authors.forename: Julia
authors.initials: J
authors.lastname: Rozenfeld
authors.forename: Deliang
authors.initials: D
authors.lastname: Huang
authors.forename: Dongyang
authors.initials: D
authors.lastname: Kang
authors.forename: Va
authors.initials: V
authors.lastname: Lip
authors.forename: Hong
authors.initials: H
authors.lastname: Fang
authors.forename: Hong
authors.initials: H
authors.lastname: Shao
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Huijun
authors.initials: H
authors.lastname: Yuan
authors.forename: Margaret
authors.initials: M
authors.lastname: Kenna
authors.forename: David T
authors.initials: DT
authors.lastname: Miller
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.forename: Weiyan
authors.initials: W
authors.lastname: Yang
authors.forename: Israel
authors.initials: I
authors.lastname: Zelikovic
authors.forename: Orah S
authors.initials: OS
authors.lastname: Platt
authors.forename: Dongyi
authors.initials: D
authors.lastname: Han
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.forename: Bai-Lin
authors.initials: BL
authors.lastname: Wu
mesh_terms: D000483:Alleles; D000818:Animals; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002681:China; D002712:Chlorides / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D034381:Hearing Loss / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017136:Ion Transport; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology; D018613:Microscopy, Confocal; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D000076988:Sulfate Transporters; D014481:United States; D014723:Vestibular Aqueduct / Q000002:abnormalities / Q000378:metabolism; D044465:White People / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: D002712:Chlorides; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters