Shivani Joshi1, Helene Kvistgaard1, Konstantinos Kamperis1, Mia Færch1, Søren Hagstrøm2, Niels Gregersen3, Søren Rittig1, Jane Hvarregaard Christensen4,5. 1. Department of Pediatrics and Adolescent Medicine and Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark. 2. Department of Pediatrics, Aalborg University Hospital, Reberbansgade 15, 9000, Aalborg, Denmark. 3. Department of Clinical Medicine - Research Unit for Molecular Medicine, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark. 4. Department of Pediatrics and Adolescent Medicine and Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark. jhc@biomed.au.dk. 5. Department of Biomedicine, Aarhus University, Bartholins Allé 6, 8000, Aarhus C, Denmark. jhc@biomed.au.dk.
Abstract
Congenital nephrogenic diabetes insipidus (CNDI) is characterized by the reduced ability of renal collecting duct cells to reabsorb water in response to the antidiuretic effect of vasopressin. Chronic polyuria and polydipsia are the hallmarks of the disease. Approximately 90% of all patients with CNDI have X-linked inherited disease caused by variants in the arginine vasopressin receptor 2 (AVPR2) gene. We present genetic findings in 34 individuals from 19 kindreds including one or more family members with CNDI. Coding regions of AVPR2 were sequenced bi-directionally. We identified eight novel disease-causing variants in AVPR2, p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro in nine kindreds. In all three families with more than one affected individual, the novel variants segregated with the disease. We also identified eight recurrent disease-causing variants, p.Val88Met, p.Leu111Valfs*80, p.Arg113Trp, p.Tyr124*, p.Ser167Leu, p.Thr207Asn, p.Arg247Alafs*12, and p.Arg337* in ten kindreds. Our findings contribute to the growing list of AVPR2 variants causing X-linked CNDI. CONCLUSION: Being a rapid diagnostic tool for CNDI, direct sequencing of AVPR2 should be encouraged in newborns with familial predisposition to CNDI. What is Known: • Disease-causing variants in AVPR2 cause X-linked congenital nephrogenic diabetes insipidus (CNDI). • DNA sequencing of AVPR2 is rapid, facilitates differential diagnosis, early intervention, and genetic diagnosis thus reducing morbidity in CNDI. What is New: • We identified eight novel disease-causing variants in AVPR2: p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro, thereby adding to the growing list of AVPR2 disease-causing variants and emphasizing the importance of genetic testing in CNDI.
Congenital nephrogenic diabetes insipidus (CNDI) is characterized by the reduced ability of renal collecting duct cells to reabsorb water in response to the antidiuretic effect of vasopressin. Chronic polyuria and polydipsia are the hallmarks of the disease. Approximately 90% of all patients with CNDI have X-linked inherited disease caused by variants in the arginine vasopressin receptor 2 (AVPR2) gene. We present genetic findings in 34 individuals from 19 kindreds including one or more family members with CNDI. Coding regions of AVPR2 were sequenced bi-directionally. We identified eight novel disease-causing variants in AVPR2, p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro in nine kindreds. In all three families with more than one affected individual, the novel variants segregated with the disease. We also identified eight recurrent disease-causing variants, p.Val88Met, p.Leu111Valfs*80, p.Arg113Trp, p.Tyr124*, p.Ser167Leu, p.Thr207Asn, p.Arg247Alafs*12, and p.Arg337* in ten kindreds. Our findings contribute to the growing list of AVPR2 variants causing X-linked CNDI. CONCLUSION: Being a rapid diagnostic tool for CNDI, direct sequencing of AVPR2 should be encouraged in newborns with familial predisposition to CNDI. What is Known: • Disease-causing variants in AVPR2 cause X-linked congenital nephrogenic diabetes insipidus (CNDI). • DNA sequencing of AVPR2 is rapid, facilitates differential diagnosis, early intervention, and genetic diagnosis thus reducing morbidity in CNDI. What is New: • We identified eight novel disease-causing variants in AVPR2: p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro, thereby adding to the growing list of AVPR2 disease-causing variants and emphasizing the importance of genetic testing in CNDI.
Authors: Mia Faerch; Thomas J Corydon; Søren Rittig; Jane H Christensen; Jens Michael Hertz; Johan Jendle Journal: Scand J Urol Nephrol Date: 2010-05-12
Authors: D G Bichet; M F Arthus; M Lonergan; G N Hendy; A J Paradis; T M Fujiwara; K Morgan; M C Gregory; W Rosenthal; A Didwania Journal: J Clin Invest Date: 1993-09 Impact factor: 14.808
Authors: D G Bichet; M Birnbaumer; M Lonergan; M F Arthus; W Rosenthal; P Goodyer; H Nivet; S Benoit; P Giampietro; S Simonetti Journal: Am J Hum Genet Date: 1994-08 Impact factor: 11.025
Authors: Mia Faerch; Jane H Christensen; Søren Rittig; Jan-Ove Johansson; Niels Gregersen; Francis de Zegher; Thomas J Corydon Journal: Am J Physiol Renal Physiol Date: 2009-10-07