title: Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families.
abstract: BACKGROUND
  Autosomal recessive distal renal tubular acidosis (dRTA) is a rare disease characterized by a hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis, and conserved glomerular filtration rate. In some cases, neurosensorial deafness is associated. dRTA is developed during the first months of life and the main manifestations are failure to thrive, vomiting, dehydration, and anorexia.
  
  
  METHODS
  Nine unrelated families were studied: seven children, a teenager, and an adult with dRTA. Hearing was preserved in four children. Coding regions of the genes responsible for recessive dRTA were analysed by Sanger sequencing.
  
  
  RESULTS
  Molecular defects were found in the genes ATP6V1B1 and ATP6V0A4. We identified three homozygous variants in ATP6V1B: a frameshift mutation (p.Ile386Hisfs*56), a nucleotide substitution in exon 10 (p.Pro346Arg), and a new splicing mutation in intron 5. Three patients were homozygous for one novel (p.Arg743Trp) and one known (p.Asp411Tyr) missense mutations in the ATP6V0A4 gene. Three patients were compound heterozygous: one proband displayed two novel mutations, the frameshift mutation p.Val52Metfs*25, and a large deletion of exons 18-21; two probands showed the missense mutation p.Asp411Tyr and as a second mutation, p.Arg194Ter and c.1691+2dup, respectively.
  
  
  CONCLUSIONS
  ATP6V0A4 and ATP6V1B1 genes were involved in recessive dRTA of Mexican families. All ATP6V1B1 mutations detected were homozygous and all patients developed sensorineural hearing loss (SNHL) early in infancy. ATP6V0A4 mutations were found in one infant and three children without SNHL, and in one teenager and one adult with SNHL confirming the phenotypic variability in this trait. The mutation p.Asp411Tyr detected in four Mexican families was due to a founder effect. Screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA in this population.
authors.affiliation: Departamento de Fisiología Facultad de Medicina Universidad Nacional Autónoma de México Mexico City Mexico.
authors.forename: Laura I
authors.initials: LI
authors.lastname: Escobar
authors.affiliation: Département de Génetique Hôpital Européen Georges Pompidou Paris France.
authors.forename: Christopher
authors.initials: C
authors.lastname: Simian
authors.affiliation: Département de Génetique Hôpital Européen Georges Pompidou Paris France.
authors.forename: Cyrielle
authors.initials: C
authors.lastname: Treard
authors.affiliation: Département de Génetique Hôpital Européen Georges Pompidou Paris France.
authors.forename: Donia
authors.initials: D
authors.lastname: Hayek
authors.affiliation: Departamento de Fisiología Facultad de Medicina Universidad Nacional Autónoma de México Mexico City Mexico.
authors.forename: Carolina
authors.initials: C
authors.lastname: Salvador
authors.affiliation: Servicio de Nefrología Hospital General del Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social (IMSS) Mexico City Mexico.
authors.forename: Norma
authors.initials: N
authors.lastname: Guerra
authors.affiliation: Servicio de Nefrología Hospital General del Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social (IMSS) Mexico City Mexico.
authors.forename: Mario
authors.initials: M
authors.lastname: Matos
authors.affiliation: Laboratorio de Investigación en Nefrología Hospital Infantil de México Federico Gómez Mexico City Mexico.
authors.forename: Mara
authors.initials: M
authors.lastname: Medeiros
authors.affiliation: Laboratorio de Investigación en Nefrología Hospital Infantil de México Federico Gómez Mexico City Mexico.
authors.forename: Sandra
authors.initials: S
authors.lastname: Enciso
authors.affiliation: UMAE Hospital de Especialidades Centro Médico Nacional del Noreste, IMSS No. 25. Monterrey Mexico.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Camargo
authors.affiliation: Département de Génetique Hôpital Européen Georges Pompidou Paris France.
authors.forename: Rosa
authors.initials: R
authors.lastname: Vargas-Poussou
keywords: Hearing loss; hypokalemia; nephrocalcinosis; renal tubular acidosis