Alternative titles; symbols
ORPHA: 223; DO: 0081061;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.12 | Diabetes insipidus, nephrogenic, 2 | 125800 | Autosomal dominant; Autosomal recessive | 3 | AQP2 | 107777 |
A number sign (#) is used with this entry because autosomal nephrogenic diabetes insipidus-2 (NDI2) is caused by heterozygous, homozygous, or compound heterozygous mutation in the gene encoding the aquaporin-2 water channel (AQP2; 107777), which maps to chromosome 12q13. Both autosomal dominant and autosomal recessive forms have been reported.
Nephrogenic diabetes insipidus (NDI) is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopressin (AVP; 192340). Approximately 90% of patients are males with the X-linked recessive form, type I (NDI1; 304800), which is caused by mutation in the gene encoding the vasopressin V2 receptor (AVPR2; 300538). The remaining 10% of patients have the autosomal form, type II (NDI2), caused by mutation in the AQP2 gene (Morello and Bichet, 2001).
Neurogenic, or central, diabetes insipidus (CDI; 125700) is caused by mutation in the gene encoding arginine vasopressin, located on 20p13.
Van Lieburg et al. (1994) reported 3 unrelated patients with NDI. All were born of consanguineous parents, indicating autosomal recessive inheritance. Onset in all patients was within the first weeks of life, with hypernatremia and severe dehydration. Urine osmolality was inappropriately low and did not increase in response to AVP. Other features included failure to thrive, feeding difficulties, and unexplained fever.
Zimmerman and Green (1975) found that a subset of patients with congenital nephrogenic diabetes insipidus showed a normal increase in urinary levels of cAMP in response to ADH, indicating that the defect was distal to the adenylate cyclase step. They termed this form 'NDI type II.' In patients with X-linked congenital nephrogenic diabetes insipidus, or NDI type I, administration of ADH was not followed by an increase in urinary cAMP (Bell et al., 1974). One of the type II cases of Zimmerman and Green (1975) was a girl, further excluding the X-linked form.
Ohzeki et al. (1984) reported an extensive Japanese kindred with NDI in which affected members showed increased cAMP excretion in response to ADH. Inheritance was clearly autosomal dominant. Nine persons spanning 4 generations were affected, with 3 instances of male-to-male transmission. Robertson and Scheidler (1981) described a form of NDI with partial resistance to vasopressin; the administration of high dosages of vasopressin was effective.
Moses et al. (1988) presented evidence of 2 distinct pathophysiologic mechanisms in NDI in an unrelated man and woman with the disorder. Whereas the male patient was thought to have a defect at the V2 receptor as measured by response to 1-desamino-8-D-arginine vasopressin (dDAVP), consistent with the X-linked form, the 25-year-old woman had normal V2 receptor activity, suggesting a defect distal to the receptor. Both patients had normal V1 receptor-mediated functions and normal G(s) activity of red cell membranes. The woman had a son with diabetes insipidus; the man had 2 daughters with normal urine-concentrating capacity.
Knoers and Monnens (1991) reported a boy with nephrogenic diabetes insipidus who had normal coagulation, fibrinolytic, and vasodilatory responses to dDAVP. Since patients with X-linked NDI and defects in the V2 receptor show blunted extrarenal responses to dDAVP administration, the authors concluded that the defect in their patient was limited to the kidney.
Both autosomal dominant (Ohzeki et al., 1984) and autosomal recessive modes of inheritance of NDI2 have been reported.
Ray et al. (1990) and Langley et al. (1991) reported a family in which 2 sisters of consanguineous Pakistani parents were affected with nephrogenic diabetes insipidus. DNA analysis using the DXS52 locus as a probe demonstrated that each sister had inherited different Xq28 regions from their mother, excluding the classic X-linked form. Karyotype results were not reported, but the gender of the patients, a history of parental consanguinity, and normal urine concentration in both parents suggested that the disorder in this family resulted from an autosomal recessive mutation.
In a male patient with nephrogenic diabetes insipidus who was originally reported by Knoers and Monnens (1991), Deen et al. (1994) identified compound heterozygosity for 2 mutations in the AQP2 gene (107777.0001; 107777.0002). Missense mutations and a single-nucleotide deletion in the AQP2 gene were found by van Lieburg et al. (1994) in 3 NDI patients from consanguineous families (107777.0003-107777.0005).
In a mother and daughter with autosomal dominant NDI, Mulders et al. (1998) identified a heterozygous mutation in the AQP2 gene (107777.0009), which had a dominant-negative effect when expressed in Xenopus oocytes.
Carroll et al. (2006) identified the molecular basis of NDI in Arab families. The authors identified 2 novel missense mutations in AQP2.
In a family traced back to 1813, Cannon (1955) reported 3 instances of male-to-male transmission of diabetes insipidus. However, Ten Bensel and Peters (1970) restudied part of Cannon's pedigree and determined that the disorder in this family showed typical X-linked inheritance.
Weller et al. (1950) and Levinger and Escamilla (1955) described autosomal dominant inheritance of diabetes insipidus; however, it was difficult to distinguish nephrogenic and neurogenic types in these reports.
Bell, N. H., Clark, C. M., Jr., Avery, S., Sinha, T., Trygstad, C. W., Allen, D. O. Demonstration of a defect in the formation of adenosine 3-prime,5-prime-monophosphate in vasopressin-resistant diabetes insipidus. Pediat. Res. 8: 223-230, 1974. [PubMed: 4362729] [Full Text: https://doi.org/10.1203/00006450-197404000-00002]
Bichet, D. G., Hendy, G. N., Lonergan, M., Arthus, M.-F., Ligier, S., Pausova, Z., Kluge, R., Zingg, H., Saenger, P., Oppenheimer, E., Hirsch, D. J., Gilgenkrantz, S., Salles, J.-P., Oberle, I., Mandel, J.-L., Gregory, M. C., Fujiwara, T. M., Morgan, K., Scriver, C. R. X-linked nephrogenic diabetes insipidus: from the ship Hopewell to RFLP studies. Am. J. Hum. Genet. 51: 1089-1102, 1992. [PubMed: 1357965]
Bode, H. H., Crawford, J. D. Nephrogenic diabetes insipidus in North America--the Hopewell hypothesis. New Eng. J. Med. 280: 750-754, 1969. [PubMed: 4886456] [Full Text: https://doi.org/10.1056/NEJM196904032801404]
Cannon, J. F. Diabetes insipidus: clinical and experimental studies with consideration of genetic relationships. AMA Arch. Intern. Med. 96: 215-272, 1955. [PubMed: 14397883] [Full Text: https://doi.org/10.1001/archinte.1955.00250130089012]
Carroll, P., Al-Mojalli, H., Al-Abbad, A., Al-Hassoun, I., Al-Hamed, M., Al-Amr, R., Butt, A. I., Meyer, B. F. Novel mutations underlying nephrogenic diabetes insipidus in Arab families. Genet. Med. 8: 443-447, 2006. [PubMed: 16845277] [Full Text: https://doi.org/10.1097/01.gim.0000223554.46981.7a]
Cutler, R. E., Kleeman, C. R., Maxwell, M. H., Dowling, J. T. Physiologic studies in nephrogenic diabetes insipidus. J. Clin. Endocr. 22: 827-838, 1962. [PubMed: 13882818] [Full Text: https://doi.org/10.1210/jcem-22-8-827]
Deen, P. M. T., Verdijk, M. A. J., Knoers, N. V. A. M., Wieringa, B., Monnens, L. A. H., van Os, C. H., van Oost, B. A. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 264: 92-94, 1994. [PubMed: 8140421] [Full Text: https://doi.org/10.1126/science.8140421]
Knoers, N., Monnens, L. A. H. A variant of nephrogenic diabetes insipidus: V2 receptor abnormality restricted to the kidney. Europ. J. Pediat. 150: 370-373, 1991. [PubMed: 1828422] [Full Text: https://doi.org/10.1007/BF01955943]
Langley, J. M., Balfe, J. W., Selander, T., Ray, P. N., Clarke, J. T. R. Autosomal recessive inheritance of vasopressin-resistant diabetes insipidus. Am. J. Med. Genet. 38: 90-94, 1991. [PubMed: 1672792] [Full Text: https://doi.org/10.1002/ajmg.1320380120]
Levinger, E. L., Escamilla, R. F. Hereditary diabetes insipidus: report of 20 cases in seven generations. J. Clin. Endocr. 15: 547-552, 1955. [PubMed: 14367471] [Full Text: https://doi.org/10.1210/jcem-15-5-547]
Morello, J.-P., Bichet, D. G. Nephrogenic diabetes insipidus. Annu. Rev. Physiol. 63: 607-630, 2001. [PubMed: 11181969] [Full Text: https://doi.org/10.1146/annurev.physiol.63.1.607]
Moses, A. M., Miller, J. L., Levine, M. A. Two distinct pathophysiological mechanisms in congenital nephrogenic diabetes insipidus. J. Clin. Endocr. Metab. 66: 1259-1264, 1988. [PubMed: 3131381] [Full Text: https://doi.org/10.1210/jcem-66-6-1259]
Mulders, S. M., Bichet, D. G., Rijss, J. P. L., Kamsteeg, E.-J., Arthus, M.-F., Lonergan, M., Fujiwara, M., Morgan, K., Leijendekker, R., van der Sluijs, P., van Os, C. H., Deen, P. M. T. An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex. J. Clin. Invest. 102: 57-66, 1998. [PubMed: 9649557] [Full Text: https://doi.org/10.1172/JCI2605]
Ohzeki, T., Igarashi, T., Okamoto, A. Familial cases of congenital nephrogenic diabetes insipidus type II: remarkable increment of urinary adenosine 3-prime,5-prime-monophosphate in response to antidiuretic hormone. J. Pediat. 104: 593-595, 1984. [PubMed: 6323666] [Full Text: https://doi.org/10.1016/s0022-3476(84)80556-9]
Ray, P. N., Selander, T., Balfe, J. W., Langley, J. M., Clarke, J. T. R. Autosomal recessive variant of nephrogenic diabetes insipidus (NDI). (Abstract) Am. J. Hum. Genet. 47 (suppl.): A74 only, 1990.
Robertson, G. L., Scheidler, J. A. A newly recognized variant of familial nephrogenic diabetes insipidus distinguished by partial resistance to vasopressin (type 2). (Abstract) Clin. Res. 29: 555A only, 1981.
Robinson, M. G., Kaplan, S. A. Inheritance of vasopressin-resistant ('nephrogenic') diabetes insipidus. AMA J. Dis. Child. 99: 164-174, 1960. [PubMed: 14437976] [Full Text: https://doi.org/10.1001/archpedi.1960.02070030166004]
Ten Bensel, R. W., Peters, E. R. Progressive hydronephrosis, hydroureter, and dilatation of the bladder in siblings with congenital nephrogenic diabetes insipidus. J. Pediat. 77: 439-443, 1970. [PubMed: 5502093] [Full Text: https://doi.org/10.1016/s0022-3476(70)80012-9]
van Lieburg, A. F., Verdijk, M. A. J., Knoers, V. V. A. M., van Essen, A. J., Proesmans, W., Mallmann, R., Monnens, L. A. H., van Oost, B. A., van Os, C. H., Deen, P. M. T. Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene. Am. J. Hum. Genet. 55: 648-652, 1994. [PubMed: 7524315]
Weller, C. G., Elliott, W., Gusman, A. R. Hereditary diabetes insipidus: unusual urinary tract changes. J. Urol. 64: 716-721, 1950. [PubMed: 14785081] [Full Text: https://doi.org/10.1016/S0022-5347(17)68700-7]
Zimmerman, D., Green, O. C. Nephrogenic diabetes insipidus type II: defect distal to the adenylate cyclase step. Pediat. Res. 9: 250 only, 1975.