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Eur J Pediatr. 2015 Oct;174(10):1373-85. doi: 10.1007/s00431-015-2534-4. Epub 2015 Apr 23.

Novel mutations associated with nephrogenic diabetes insipidus. A clinical-genetic study.

Author information

1
BioCruces Institute, Ciberer, Cruces University Hospital, Bizkaia, Spain. algarcia12@hotmail.com.
2
BioCruces Institute, Ciberer, Cruces University Hospital, Bizkaia, Spain. gustavo.perezdenanclaresleal@osakidetza.net.
3
Paediatric Nephrology, Cruces University Hospital, Bizkaia, Spain. leyre.madariagadominguez@osakidetza.net.
4
Department of Paediatrics, School of Medicine and Odontology, University of Basque Country UPV/EHU, Bizkaia, Spain. leyre.madariagadominguez@osakidetza.net.
5
Paediatric Nephrology, Cruces University Hospital, Bizkaia, Spain. mireia.aguirremenica@osakidetza.net.
6
Paediatric Nephrology, University Hospital Vall d'Hebron, Barcelona, Spain. schocron@vhebron.net.
7
Paediatric Nephrology, University Hospital Vall d'Hebron, Barcelona, Spain. amadrid@vhebron.net.
8
Endocrinology Service, Complejo Hospitalario de Navarra, Pamplona, Spain. javier.lafita.tejedor@cfnavarra.es.
9
Paediatric Research and Metabolism Unit, Reina Sofia University Hospital, Córdoba, Spain. mercedes_gil_campos@yahoo.es.
10
Department of Paediatrics, Division of Endocrinology, 12 de Octubre Hospital, Madrid, Spain. jsanchez.hdoc@salud.madrid.org.
11
Paediatric Endocrinology, Albacete General University Hospital, Albacete, Spain. rruizc@sescam.jccm.es.
12
Paediatric Nephrology, 12 de Octubre Hospital, Madrid, Spain. mar.espino@salud.madrid.org.
13
Department of Paediatrics, Motril Hospital, Granada, Spain. gomezvida@gmail.com.
14
Paediatric Nephrology, Asturias Central University Hospital, Oviedo, Asturias, Spain. fsantos@uniovi.es.
15
Paediatric Nephrology, Nuestra Señora de Candelaria University Hospital, Tenerife, Canarias, Spain. vgarcianieto@gmail.com.
16
Nephrology Unit, Cayetano Heredia University, Cayetano Heredia Hospital, Lima, Peru. reyfe@hotmail.com.
17
León Hospital, León, Spain. elem12lm23@gmail.com.
18
Paediatric Nephrology Department, Materno Infantil Hospital, Badajoz, Spain. ehidalgo@unex.es.
19
Department of Paediatrics, Aristotle University of Thessaloniki, Hippokratio Hospital, Thessaloniki, Greece. nprintza@gmail.com.
20
Paediatric Nephrology Department, Sant Joan de Déu Hospital, Barcelona, Spain. jcamacho@hsjdbcn.org.
21
BioCruces Institute, Ciberer, Cruces University Hospital, Bizkaia, Spain. luisantonio.castanogonzalez@osakidetza.net.
22
Department of Paediatrics, School of Medicine and Odontology, University of Basque Country UPV/EHU, Bizkaia, Spain. luisantonio.castanogonzalez@osakidetza.net.
23
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain, . luisantonio.castanogonzalez@osakidetza.net.
24
Paediatric Nephrology, University Hospital Vall d'Hebron, Barcelona, Spain. gariceta@vhebron.net.
25
Autonomous University of Barcelona, Barcelona, Spain. gariceta@vhebron.net.

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.

CONCLUSION:

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.

WHAT IS KNOWN:

• 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.

KEYWORDS:

AQP2; AVPR2; Heterozygous females; Nephrogenic diabetes insipidus

PMID:
25902753
DOI:
10.1007/s00431-015-2534-4
[Indexed for MEDLINE]

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