Genetic investigation of autosomal recessive distal renal tubular acidosis: evidence for early sensorineural hearing loss associated with mutations in the ATP6V0A4 gene.
Mutations in the ATP6V1B1 and ATP6V0A4 genes, encoding subunits B1 and 4 of apical H(+) ATPase, cause recessive forms of distal renal tubular acidosis (dRTA). ATP6V1B mutations have been associated with early sensorineural hearing loss (SNHL), whereas ATP6V0A4 mutations are classically associated with either late-onset SNHL or normal hearing. The phenotype and genotype of 39 new kindreds with recessive dRTA, 18 of whom were consanguineous, were assessed. Novel and known loss-of-function mutations were identified in 31 kindreds. Fourteen new and five recurrent mutations of the ATP6V0A4 gene were identified in 21 families. For the ATP6V1B1 gene, two new and two previously described mutations were identified in 10 families. Surprisingly, seven probands with ATP6V0A4 gene mutations developed severe early SNHL between the ages of 2 mo and 10 yr. No mutation was detected in eight families. These data extend the spectrum of disease-causing mutations and provide evidence for genetic heterogeneity in SNHL. The data also demonstrate that mutations in either of these genes may cause early deafness, and they highlight the importance of genetic screening for recessive forms of dRTA independent of hearing status.
Vargas-Poussou
Rosa
R
Centre Hospitalier Universitaire de Rouen, Département de Pédiatrie Médicale, and Faculté de Médecine et de Pharmacie, Rouen, France. rosa.vargas-poussou@chu-rouen.fr
Houillier
Pascal
P
Le Pottier
Nelly
N
Strompf
Laurence
L
Loirat
Chantal
C
Baudouin
Véronique
V
Macher
Marie-Alice
MA
Déchaux
Michèle
M
Ulinski
Tim
T
Nobili
François
F
Eckart
Philippe
P
Novo
Robert
R
Cailliez
Mathilde
M
Salomon
Rémi
R
Nivet
Hubert
H
Cochat
Pierre
P
Tack
Ivan
I
Fargeot
Anne
A
Bouissou
François
F
Kesler
Gwenaelle Roussey
GR
Lorotte
Stéphanie
S
Godefroid
Nathalie
N
Layet
Valérie
V
Morin
Gilles
G
Jeunemaître
Xavier
X
Blanchard
Anne
A
D000141:Acidosis, Renal Tubular / Q000453:epidemiology* / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D025063:Chromosome Disorders / Q000453:epidemiology / Q000235:genetics; D002874:Chromosome Mapping; D015897:Comorbidity; D004252:DNA Mutational Analysis; D019317:Evidence-Based Medicine; D005260:Female; D005602:France / Q000453:epidemiology; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005820:Genetic Testing / Q000379:methods*; D006319:Hearing Loss, Sensorineural / Q000453:epidemiology* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D009154:Mutation; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors
C501005:MT-ATP6 protein, human; D025261:Mitochondrial Proton-Translocating ATPases