title: Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?
abstract: Hearing loss with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene encoding pendrin, a transmembrane Cl(-)/I(-)/HCO(3)(-) exchanger. Pendrin's critical transport substrates are thought to be I(-) in the thyroid gland and HCO(3)(-) in the inner ear. We previously reported that bi-allelic SLC26A4 mutations are associated with Pendred syndromic EVA whereas one or zero mutant alleles are associated with nonsyndromic EVA. One study proposed a correlation of nonsyndromic EVA with SLC26A4 alleles encoding pendrin with residual transport activity. Here we describe the phenotypes and SLC26A4 genotypes of 47 EVA patients ascertained since our first report of 39 patients. We sought to determine the pathogenic potential of each variant in our full cohort of 86 patients. We evaluated the trafficking of 11 missense pendrin products expressed in COS-7 cells. Products that targeted to the plasma membrane were expressed in Xenopus oocytes for measurement of anion exchange activity. p.F335L, p.C565Y, p.L597S, p.M775T, and p.R776C had Cl(-)/I(-) and Cl(-)/HCO(3)(-) exchange rate constants that ranged from 13 to 93% of wild type values. p.F335L, p.L597S, p.M775T and p.R776C are typically found as mono-allelic variants in nonsyndromic EVA. The high normal control carrier rate for p.L597S indicates it is a coincidentally detected nonpathogenic variant in this context. We observed moderate differential effects of hypo-functional variants upon exchange of HCO(3)(-) versus I(-) but their magnitude does not support a causal association with nonsyndromic EVA. However, these alleles could be pathogenic in trans configuration with a mutant allele in Pendred syndrome.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.
authors.forename: Byung Yoon
authors.initials: BY
authors.lastname: Choi
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Stewart
authors.forename: Anne C
authors.initials: AC
authors.lastname: Madeo
authors.forename: Shannon P
authors.initials: SP
authors.lastname: Pryor
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lenhard
authors.forename: Rick
authors.initials: R
authors.lastname: Kittles
authors.forename: David
authors.initials: D
authors.lastname: Eisenman
authors.forename: H Jeffrey
authors.initials: HJ
authors.lastname: Kim
authors.forename: John
authors.initials: J
authors.lastname: Niparko
authors.forename: James
authors.initials: J
authors.lastname: Thomsen
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Arnos
authors.forename: Walter E
authors.initials: WE
authors.lastname: Nance
authors.forename: Kelly A
authors.initials: KA
authors.lastname: King
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Zalewski
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Brewer
authors.forename: Thomas
authors.initials: T
authors.lastname: Shawker
authors.forename: James C
authors.initials: JC
authors.lastname: Reynolds
authors.forename: John A
authors.initials: JA
authors.lastname: Butman
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Karniski
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Griffith
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D021381:Protein Transport; D000076988:Sulfate Transporters; D013577:Syndrome; D014162:Transfection; D014723:Vestibular Aqueduct / Q000002:abnormalities / Q000378:metabolism*; D014981:Xenopus
chemical_list: D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters