title: The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis.
abstract: Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient.
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Palazzo
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Aldesia
authors.initials: A
authors.lastname: Provenzano
authors.affiliation: Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Becherucci
authors.affiliation: Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Sansavini
authors.affiliation: Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzinghi
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Orlandini
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Giunti
authors.affiliation: Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Roperto
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Pantaleo
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Rosangela
authors.initials: R
authors.lastname: Artuso
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Andreucci
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bargiacchi
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Traficante
authors.affiliation: Endocrinology Unit, Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Stagi
authors.affiliation: Pediatric Nephrology Dialysis and Transplant Unit, Department of Pediatrics, University of Padua, Padua, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Murer
authors.affiliation: Pediatric Nephrology Dialysis and Transplant Unit, Department of Pediatrics, University of Padua, Padua, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.affiliation: Nephrology Dialysis, Transplant, Bambin Gesù Children's Hospital, Roma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Emma
authors.affiliation: Pediatric Nephrology and Dialysis Unit, Children's Hospital Giovanni XXIII, Bari, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Giordano
authors.affiliation: Medical Genetic Service, Department of Laboratory, S. Chiara Hospital, Trento, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rivieri
authors.affiliation: Division of Nephrology, Dialysis and Renal Transplantation, Niguarda Ca'Granda Hospital, Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Colussi
authors.affiliation: Medical Genetics Unit, Department of Laboratory Medicine, Niguarda Ca'Granda Hospital, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Penco
authors.affiliation: Medical Genetics Unit, Department of Laboratory Medicine, Niguarda Ca'Granda Hospital, Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Manfredini
authors.affiliation: Nephrology and Dialysis Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Caruso
authors.affiliation: Genetics Unit, Department of Obstetrics and Paediatrics, IRCCS S. Maria Nuova Hospital, Reggio Emilia, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.affiliation: Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco, Italy.
authors.forename: Simeone
authors.initials: S
authors.lastname: Andrulli
authors.affiliation: Pediatric Unit, Ospedale degli Infermi, Rimini, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Vergine
authors.affiliation: Pediatric Unit, Azienda Ospedaliera Spedali Civili, Brescia, Italy.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Miglietti
authors.affiliation: Division of Nephrology, Dialysis and Hypertension, Policlinico S. Orsola-Malpighi, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Mancini
authors.affiliation: Department of Medical Sciences, Section of Pediatrics, University of Ferrara, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Malaventura
authors.affiliation: Medical Genetics, Department of Clinical and Experimental Medicine, University Hospital of Parma, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Percesepe
authors.affiliation: Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Grosso
authors.affiliation: Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Materassi
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy; Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy; Excellence Center DENOTHE, University of Florence, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy; Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy. Electronic address: s.giglio@meyer.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D035583:Rare Diseases / Q000235:genetics*; D051436:Renal Insufficiency, Chronic / Q000235:genetics*; D012189:Retrospective Studies; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*; D055815:Young Adult
chemical_list: C509766:ATP6V1B1 protein, human; D001457:Anion Exchange Protein 1, Erythrocyte; C454201:SLC4A1 protein, human; C490181:ATP6V0A4 protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: chronic kidney disease; deafness; distal renal tubular acidosis; mutations; nephrocalcinosis