title: Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34.
abstract: Failure of distal nephrons to excrete excess acid results in the "distal renal tubular acidoses" (dRTA). Early childhood features of autosomal recessive dRTA include severe metabolic acidosis with inappropriately alkaline urine, poor growth, rickets, and renal calcification. Progressive bilateral sensorineural hearing loss (SNHL) is evident in approximately one-third of patients. We have recently identified mutations in ATP6B1, encoding the B-subunit of the collecting-duct apical proton pump, as a cause of recessive dRTA with SNHL. We now report the results of genetic analysis of 13 kindreds with recessive dRTA and normal hearing. Analysis of linkage and molecular examination of ATP6B1 indicated that mutation in ATP6B1 rarely, if ever, accounts for this phenotype, prompting a genomewide linkage search for loci underlying this trait. The results strongly supported linkage with locus heterogeneity to a segment of 7q33-34, yielding a maximum multipoint LOD score of 8.84 with 68% of kindreds linked. The LOD-3 support interval defines a 14-cM region flanked by D7S500 and D7S688. That 4 of these 13 kindreds do not support linkage to rdRTA2 and ATP6B1 implies the existence of at least one additional dRTA locus. These findings establish that genes causing recessive dRTA with normal and impaired hearing are different, and they identify, at 7q33-34, a new locus, rdRTA2, for recessive dRTA with normal hearing.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 2XY, United Kingdom. fek1000@hermes.cam.ac.uk.
authors.forename: F E
authors.initials: FE
authors.lastname: Karet
authors.forename: K E
authors.initials: KE
authors.lastname: Finberg
authors.forename: A
authors.initials: A
authors.lastname: Nayir
authors.forename: A
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: S
authors.initials: S
authors.lastname: Ozen
authors.forename: S A
authors.initials: SA
authors.lastname: Hulton
authors.forename: S A
authors.initials: SA
authors.lastname: Sanjad
authors.forename: E A
authors.initials: EA
authors.lastname: Al-Sabban
authors.forename: J F
authors.initials: JF
authors.lastname: Medina
authors.forename: R P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000503:physiopathology; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D027321:Anion Transport Proteins; D017920:Antiporters; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006309:Hearing / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007223:Infant; D007231:Infant, Newborn; D008126:Lod Score; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008877:Middle East; D008969:Molecular Sequence Data; D010154:Pakistan; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D064606:SLC4A Proteins
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; D008565:Membrane Proteins; D064606:SLC4A Proteins; D000251:Adenosine Triphosphatases