title: Novel mutations associated with nephrogenic diabetes insipidus. A clinical-genetic study.
abstract: Molecular diagnosis is a useful diagnostic tool in primary nephrogenic diabetes insipidus (NDI), an inherited disease characterized by renal inability to concentrate urine. The AVPR2 and AQP2 genes were screened for mutations in a cohort of 25 patients with clinical diagnosis of NDI. Patients presented with dehydration, polyuria-polydipsia, failure to thrive (mean ± SD; Z-height -1.9 ± 2.1 and Z-weight -2.4 ± 1.7), severe hypernatremia (mean ± SD; Na 150 ± 10 mEq/L), increased plasma osmolality (mean ± SD; 311 ± 18 mOsm/Kg), but normal glomerular filtration rate. Genetic diagnosis revealed that 24 male patients were hemizygous for 17 different putative disease-causing mutations in the AVPR2 gene (each one in a different family). Of those, nine had not been previously reported, and eight were recurrent. Moreover, we found those same AVPR2 changes in 12 relatives who were heterozygous carriers. Further, in one female patient, AVPR2 gene study turned out to be negative and she was found to be homozygous for the novel AQP2 p.Ala86Val alteration.
  
  
  CONCLUSIONS
  Genetic analysis presumably confirmed the diagnosis of nephrogenic diabetes insipidus in every patient of the studied cohort. We emphasize that we detected a high presence (50 %) of heterozygous females with clinical NDI symptoms.
  
  
  BACKGROUND
  • In most cases (90 %), inherited nephrogenic diabetes insipidus (NDI) is an X-linked disease, caused by mutations in the AVPR2 gene. • In rare occasions (10 %), it is caused by mutations in the AQP2 gene. What is new: • In this study, we report 10 novel mutations associated with NDI. • We have detected a high presence (50 %) of heterozygous carriers with clinical NDI symptoms.
authors.affiliation: BioCruces Institute, Ciberer, Cruces University Hospital, Bizkaia, Spain. algarcia12@hotmail.com.
authors.forename: Alejandro
authors.initials: A
authors.lastname: García Castaño
authors.affiliation: BioCruces Institute, Ciberer, Cruces University Hospital, Bizkaia, Spain. gustavo.perezdenanclaresleal@osakidetza.net.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pérez de Nanclares
authors.affiliation: Paediatric Nephrology, Cruces University Hospital, Bizkaia, Spain. leyre.madariagadominguez@osakidetza.net.|Department of Paediatrics, School of Medicine and Odontology, University of Basque Country UPV/EHU, Bizkaia, Spain. leyre.madariagadominguez@osakidetza.net.
authors.forename: Leire
authors.initials: L
authors.lastname: Madariaga
authors.affiliation: Paediatric Nephrology, Cruces University Hospital, Bizkaia, Spain. mireia.aguirremenica@osakidetza.net.
authors.forename: Mireia
authors.initials: M
authors.lastname: Aguirre
authors.affiliation: Paediatric Nephrology, University Hospital Vall d'Hebron, Barcelona, Spain. schocron@vhebron.net.
authors.forename: Sara
authors.initials: S
authors.lastname: Chocron
authors.affiliation: Paediatric Nephrology, University Hospital Vall d'Hebron, Barcelona, Spain. amadrid@vhebron.net.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Madrid
authors.affiliation: Endocrinology Service, Complejo Hospitalario de Navarra, Pamplona, Spain. javier.lafita.tejedor@cfnavarra.es.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Lafita Tejedor
authors.affiliation: Paediatric Research and Metabolism Unit, Reina Sofia University Hospital, Córdoba, Spain. mercedes_gil_campos@yahoo.es.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gil Campos
authors.affiliation: Department of Paediatrics, Division of Endocrinology, 12 de Octubre Hospital, Madrid, Spain. jsanchez.hdoc@salud.madrid.org.
authors.forename: Jaime
authors.initials: J
authors.lastname: Sánchez Del Pozo
authors.affiliation: Paediatric Endocrinology, Albacete General University Hospital, Albacete, Spain. rruizc@sescam.jccm.es.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ruiz Cano
authors.affiliation: Paediatric Nephrology, 12 de Octubre Hospital, Madrid, Spain. mar.espino@salud.madrid.org.
authors.forename: Mar
authors.initials: M
authors.lastname: Espino
authors.affiliation: Department of Paediatrics, Motril Hospital, Granada, Spain. gomezvida@gmail.com.
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Gomez Vida
authors.affiliation: Paediatric Nephrology, Asturias Central University Hospital, Oviedo, Asturias, Spain. fsantos@uniovi.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos
authors.affiliation: Paediatric Nephrology, Nuestra Señora de Candelaria University Hospital, Tenerife, Canarias, Spain. vgarcianieto@gmail.com.
authors.forename: Victor Manuel
authors.initials: VM
authors.lastname: García Nieto
authors.affiliation: Nephrology Unit, Cayetano Heredia University, Cayetano Heredia Hospital, Lima, Peru. reyfe@hotmail.com.
authors.forename: Reyner
authors.initials: R
authors.lastname: Loza
authors.affiliation: León Hospital, León, Spain. elem12lm23@gmail.com.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Rodríguez
authors.affiliation: Paediatric Nephrology Department, Materno Infantil Hospital, Badajoz, Spain. ehidalgo@unex.es.
authors.forename: Emilia
authors.initials: E
authors.lastname: Hidalgo Barquero
authors.affiliation: Department of Paediatrics, Aristotle University of Thessaloniki, Hippokratio Hospital, Thessaloniki, Greece. nprintza@gmail.com.
authors.forename: Nikoleta
authors.initials: N
authors.lastname: Printza
authors.affiliation: Paediatric Nephrology Department, Sant Joan de Déu Hospital, Barcelona, Spain. jcamacho@hsjdbcn.org.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Camacho
authors.affiliation: BioCruces Institute, Ciberer, Cruces University Hospital, Bizkaia, Spain. luisantonio.castanogonzalez@osakidetza.net.|Department of Paediatrics, School of Medicine and Odontology, University of Basque Country UPV/EHU, Bizkaia, Spain. luisantonio.castanogonzalez@osakidetza.net.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain, . luisantonio.castanogonzalez@osakidetza.net.
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
authors.affiliation: Paediatric Nephrology, University Hospital Vall d'Hebron, Barcelona, Spain. gariceta@vhebron.net.|Autonomous University of Barcelona, Barcelona, Spain. gariceta@vhebron.net.
authors.forename: Gema
authors.initials: G
authors.lastname: Ariceta
mesh_terms: D051399:Aquaporin 2 / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D018500:Diabetes Insipidus, Nephrogenic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: C496023:AQP2 protein, human; D051399:Aquaporin 2; D004247:DNA
keywords: AQP2; AVPR2; Heterozygous females; Nephrogenic diabetes insipidus