Juan Gómez1, Helena Gil-Peña2, Fernando Santos2,3, Eliecer Coto1,4, Ana Arango1, Olaya Hernandez3, Julián Rodríguez2, Inmaculada Nadal5, Virginia Cantos6, Sara Chocrón7, Inés Vergara8, Álvaro Madrid7, Carlos Vazquez9, Luz E González10, Fiona Blanco11. 1. Department of Molecular Genetics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain. 2. Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain. 3. Department of Pediatrics, Universidad de Oviedo, Oviedo, Asturias, Spain. 4. Red de Investigación Renal - REDINREN, Madrid, Madrid, Spain. 5. Department of Pediatrics, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain. 6. Department of Pediatrics, Hospital Infanta Elena, Huelva, Andalucía, Spain. 7. Department of Pediatrics, Hospital Vall d`Hebron, Barcelona, Barcelona, Spain. 8. Department of Pediatrics, Hospital Materno-Infantil Teresa Herrera, A Coruña, Galicia, Spain. 9. Department of Molecular Genetics, Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canaria, Canarias, Spain. 10. Department of Pediatrics, Fundación Cardio Infantil, Bogotá, Colombia. 11. Department of Pediatrics, IIS-Fundación Jiménez Díaz, Madrid, Madrid, Spain.
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. CONCLUSION: 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.
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. CONCLUSION: 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.
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