title: Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.
abstract: Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.
authors.affiliation: Department of Medical Genetics, University of Cambridge, UK.
authors.forename: E H
authors.initials: EH
authors.lastname: Stover
authors.forename: K J
authors.initials: KJ
authors.lastname: Borthwick
authors.forename: C
authors.initials: C
authors.lastname: Bavalia
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authors.lastname: Eady
authors.forename: D M
authors.initials: DM
authors.lastname: Fritz
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authors.initials: N
authors.lastname: Rungroj
authors.forename: A B S
authors.initials: AB
authors.lastname: Giersch
authors.forename: C C
authors.initials: CC
authors.lastname: Morton
authors.forename: P R
authors.initials: PR
authors.lastname: Axon
authors.forename: I
authors.initials: I
authors.lastname: Akil
authors.forename: E A
authors.initials: EA
authors.lastname: Al-Sabban
authors.forename: D M
authors.initials: DM
authors.lastname: Baguley
authors.forename: S
authors.initials: S
authors.lastname: Bianca
authors.forename: A
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: Z
authors.initials: Z
authors.lastname: Bircan
authors.forename: D
authors.initials: D
authors.lastname: Chauveau
authors.forename: M-J
authors.initials: MJ
authors.lastname: Clermont
authors.forename: A
authors.initials: A
authors.lastname: Guala
authors.forename: S A
authors.initials: SA
authors.lastname: Hulton
authors.forename: H
authors.initials: H
authors.lastname: Kroes
authors.forename: G
authors.initials: G
authors.lastname: Li Volti
authors.forename: S
authors.initials: S
authors.lastname: Mir
authors.forename: H
authors.initials: H
authors.lastname: Mocan
authors.forename: A
authors.initials: A
authors.lastname: Nayir
authors.forename: S
authors.initials: S
authors.lastname: Ozen
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez Soriano
authors.forename: S A
authors.initials: SA
authors.lastname: Sanjad
authors.forename: V
authors.initials: V
authors.lastname: Tasic
authors.forename: C M
authors.initials: CM
authors.lastname: Taylor
authors.forename: R
authors.initials: R
authors.lastname: Topaloglu
authors.forename: A N
authors.initials: AN
authors.lastname: Smith
authors.forename: F E
authors.initials: FE
authors.lastname: Karet
mesh_terms: D000141:Acidosis, Renal Tubular / Q000201:enzymology / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D007758:Ear, Inner / Q000201:enzymology; D004848:Epithelium / Q000201:enzymology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005808:Genes, Recessive / Q000235:genetics; D008040:Genetic Linkage; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D006180:Proton-Translocating ATPases / Q000235:genetics*
chemical_list: D004247:DNA; D006180:Proton-Translocating ATPases