| #125800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| DIABETES INSIPIDUS, NEPHROGENIC, TYPE II | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because autosomal nephrogenic diabetes insipidus (NDI) is caused by mutation in the gene encoding the aquaporin-2 water channel (AQP2; 107777), which maps to chromosome 12q. Both autosomal dominant and autosomal recessive forms have been reported. An X-linked form (304800) exists as well. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nephrogenic diabetes insipidus 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 (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, 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inheritance | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Both autosomal dominant (Ohzeki et al., 1984) and autosomal recessive modes of inheritance 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a male patient with nephrogenic diabetes insipidus 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| History | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bichet et al. (1992); Bode and Crawford (1969); Cutler et al. (1955); Robinson and Kaplan (1960) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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