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Report of 33 Novel AVPR2 Mutations and Analysis of 117 Families with X-Linked Nephrogenic Diabetes Insipidus

MARIE-FRANÇOISE ARTHUS^*, MICHÈLE LONERGAN^*, M. JOYCE CRUMLEY^||, ANNA K. NAUMOVA^,§, DENIS MORIN^¶, LUIZ A. DE MARCO^#, BERNARD S. KAPLAN^**, GARY L. ROBERTSON, SEI SASAKI, KENNETH MORGAN^,,||, DANIEL G. BICHET^* and T. MARY FUJIWARA^,,||

^* Department of Medicine, Université de Montréal and Research Centre, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Department of Human Genetics, McGill University, Montreal, Canada
Department of Medicine, McGill University, Montreal, Canada
^§ Department of Obstetrics and Gynecology, McGill University, Montreal, Canada
^|| Montreal General Hospital Research Institute, Montreal, Canada
^¶ Unité 469, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique-INSERM de Pharmacologie-Endocrinologie, Montpellier, France
^# Department of Pharmacology, University Federal de Minas Gerais, Belo Horizonte, Brazil
^** Division of Nephrology, The Children's Hospital of Philadelphia and Department of Pediatrics, The University of Pennsylvania, Philadelphia, Pennsylvania
Clinical Research Center and Northwestern University Medical School, Chicago, Illinois
Second Department of Internal Medicine, School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Correspondence to Dr. Daniel G. Bichet, Centre de Recherche, Hôpital du Sacré-Coeur de Montréal, 5400, Boulevard Gouin Ouest, Montréal (Québec) H4J 1C5 Canada. Phone: 514-338-2486; Fax: 514-338-2694; E-mail: D-Binette{at}crhsc.umontreal.ca

Abstract. X-linked nephrogenic diabetes insipidus (NDI) is a rare disease caused by mutations in the arginine vasopressin receptor 2 gene (AVPR2). Thirty-three novel AVPR2 mutations were identified in 62 families that were not included in our previous studies. This study describes the diversity of mutations observed in a total of 117 families, the number of affected people at the time of diagnosis, skewed X chromosome inactivation in severely affected females, the inferred parental origin of de novo mutations, and it provides estimates of incidence. Among 117 families, there were 82 different putative disease-causing mutations. Based on haplotype analysis, it can be inferred that when the same AVPR2 mutation is identified in different families that were not known to be related, the mutations most likely arose independently. More than half of the families had only one affected male; two families presented with a severely affected female and no family history of NDI. A de novo mutation arose during oogenesis in the mother in 20% of isolated cases. The estimate of about 8.8 per million male live births of the incidence of X-linked NDI in the province of Quebec, Canada may be representative of the general population except in Nova Scotia and New Brunswick, where the incidence is more than six times higher. Documentation of the diversity of mutations will assist in revealing the full spectrum of clinical variation. Discussion of genetic and population genetic aspects of X-linked NDI may contribute to early diagnosis and treatment.

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