title: Primary distal renal tubular acidosis: novel findings in patients studied by next-generation sequencing.
abstract: BACKGROUND
  Primary distal renal tubular acidosis (DRTA) is a rare disease caused by loss-of-function mutations in at least three genes (ATP6V0A4, ATP6V1B1, and SLC4A1) involved in urinary distal acidification. The next-generation sequencing (NGS) technique facilitates the search for mutations in DRTA patients and helps to characterize the genetic and clinical spectrum of the disease.
  
  
  METHODS
  Ten DRTA patients were studied. They had normal serum anion gap (AG), metabolic acidosis with simultaneous positive urinary AG, and inability to maximally acidify the urine. The exons of the three genes were sequenced in two pools by ultrasequencing. Putative mutations were confirmed by corresponding Sanger sequencing of each exon.
  
  
  RESULTS
  We found 13 mutations in nine patients. ATP6V0A4: Intron16+2insA; p.R807Q; p.Q276fs; p.P395fs; Intron7-2T>C. ATP6V1B1: p.I386fs; p.R394Q. SLC4A1: p.V245M; p.R589C; p.R589H; p.G609A. One case was a compound heterozygous with a known mutation in ATP6V1B1 (p.G609R) and a pathogenic variation at SLC4A1 (p.E508K). One patient was negative for mutations.
  
  
  CONCLUSIONS
  This study evidences that NGS is labor and cost effective for the analysis of DRTA genes. Our results show for the first time SLC4A1 gene mutations in Spanish patients and disclose that compound heterozygosity at two different genes can be responsible for DRTA.
authors.affiliation: Department of Molecular Genetics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Gómez
authors.affiliation: Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Gil-Peña
authors.affiliation: Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.|Department of Pediatrics, Universidad de Oviedo, Oviedo, Asturias, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos
authors.affiliation: Department of Molecular Genetics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.|Red de Investigación Renal - REDINREN, Madrid, Madrid, Spain.
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.affiliation: Department of Molecular Genetics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Arango
authors.affiliation: Department of Pediatrics, Universidad de Oviedo, Oviedo, Asturias, Spain.
authors.forename: Olaya
authors.initials: O
authors.lastname: Hernandez
authors.affiliation: Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Rodríguez
authors.affiliation: Department of Pediatrics, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Nadal
authors.affiliation: Department of Pediatrics, Hospital Infanta Elena, Huelva, Andalucía, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Cantos
authors.affiliation: Department of Pediatrics, Hospital Vall d`Hebron, Barcelona, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Chocrón
authors.affiliation: Department of Pediatrics, Hospital Materno-Infantil Teresa Herrera, A Coruña, Galicia, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Vergara
authors.affiliation: Department of Pediatrics, Hospital Vall d`Hebron, Barcelona, Barcelona, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Madrid
authors.affiliation: Department of Molecular Genetics, Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canaria, Canarias, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vazquez
authors.affiliation: Department of Pediatrics, Fundación Cardio Infantil, Bogotá, Colombia.
authors.forename: Luz E
authors.initials: LE
authors.lastname: González
authors.affiliation: Department of Pediatrics, IIS-Fundación Jiménez Díaz, Madrid, Madrid, Spain.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blanco
mesh_terms: D000136:Acid-Base Equilibrium; D000138:Acidosis / Q000097:blood; D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D003362:Cost-Benefit Analysis; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation