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 vasopression (AVP; 192340). Approximately 90% of patients are males with the X-linked ... 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 vasopression (AVP; 192340). Approximately 90% of patients are males with the X-linked recessive form (type I), which is caused by a defect in the vasopressin V2 receptor in renal collecting duct cells. The remaining 10% of patients have autosomal NDI (125800) (type II), which is caused by mutations in the gene encoding the aquaporin-2 water channel (AQP2; 107777) on chromosome 12q13 (Morello and Bichet, 2001). Neurogenic, or central, diabetes insipidus (125700) is caused by mutation in the gene encoding arginine vasopression, located on 20p13.
In a Mormon family traced to 1813, Cannon (1955) reported 3 instances of male-to-male transmission of diabetes insipidus. However, he noted reduced penetrance in females, as carriers did not show the disorder. Thus was raised the suspicion that ... In a Mormon family traced to 1813, Cannon (1955) reported 3 instances of male-to-male transmission of diabetes insipidus. However, he noted reduced penetrance in females, as carriers did not show the disorder. Thus was raised the suspicion that the disorder in this family was actually X-linked. Cutler et al. (1955) proved the renal basis of the disorder in this family. Ten Bensel and Peters (1970) described hydronephrosis in affected male sibs of the family reported by Cannon (1955). They determined that the pedigree, covering 5 generations with 12 affected males, was typical of X linkage. Nakano (1969) described familial nephrogenic diabetes insipidus in 4 generations of a Samoan family. Van Lieburg et al. (1999) made a retrospective analysis of clinical data from 30 male nephrogenic diabetes insipidus patients, aged 1 month to 40 years, from 18 Dutch families. In 28 patients, 17 different mutations in the AVPR2 gene were found. Two patients had mutations in the AQP2 gene. Eighty-seven percent of the patients were diagnosed within the first 2.5 years of life. Main symptoms at clinical presentation were vomiting and anorexia, failure to thrive, fever, and constipation. Most patients were on hydrochlorothiazide-amiloride treatment without significant side effects. Two patients suffered from severe hydronephrosis with a small rupture of the urinary tract after a minor trauma, and 2 patients experienced episodes of acute urine retention. Height SD scores for age remained below the 50th percentile in the majority of patients, whereas weight for height SD scores showed catch-up after several years of being underweight. The majority of patients were found to have normal intelligence; this was in contrast to the belief that mental retardation is the most frequent long-term sequela of NDI. Except for a possibly milder phenotype in patients with an AVPR2 G185C mutation (300538.0003), no clear relationship between clinical and genetic data could be found.
In 2 unrelated patients with X-linked NDI, Rosenthal et al. (1992) identified 2 different mutations in the AVPR2 gene (300538.0001; 300538.0002). One of the patients was a 37-year-old man with a lifelong history of polyuria, polydipsia, and mental ... In 2 unrelated patients with X-linked NDI, Rosenthal et al. (1992) identified 2 different mutations in the AVPR2 gene (300538.0001; 300538.0002). One of the patients was a 37-year-old man with a lifelong history of polyuria, polydipsia, and mental retardation resulting from repeated and prolonged episodes of dehydration in the first year of life. In 3 unrelated patients with X-linked nephrogenic diabetes insipidus, van den Ouweland et al. (1992) identified 3 different mutations in the AVPR2 gene (300538.0003-300538.0005). All of the mutations occurred in a highly conserved extracellular domain. Bichet (1994) indicated that a total of 30 different mutations had been identified in the AVPR2 gene, distributed among 37 families. About half of these represented missense mutations. He emphasized the usefulness of early detection of the mutation in the neonate to prevent the adverse effects of dehydration. In 5 Arab families with nephrogenic diabetes insipidus, Carroll et al. (2006) 1 novel missense mutation in AVPR2, 1 previously reported missense mutation in AVPR2, and 1 novel contiguous gene deletion involving AVPR2. - Skewed X Inactivation The possibility of skewed X inactivation was invoked by van Lieburg et al. (1995), who described 3 NDI families in which females showed clinical features resembling those of males. DNA analysis indicated that each was heterozygous for a specific AVPR2 mutation, as were also 2 asymptomatic female family members. The authors concluded that, in female NDI patients, the possibility of heterozygosity for an AVPR2 gene mutation has to be considered in addition to homozygosity for mutations in the AQP2 gene located on chromosome 12. In 6 members of a Japanese family with X-linked NDI, Nomura et al. (1997) identified a mutation in the AVPR2 gene (300538.0013). Three heterozygous females had differences in clinical severity of NDI. The X-inactivation patterns of these females were investigated by studying the methylated trinucleotide repeat in the human androgen receptor gene. The grandmother showed extremely skewed methylation of one X chromosome, while her daughter had moderately skewed methylation. The daughter of the grandmother's sister, who had no symptoms of NDI, showed random methylation. Nomura et al. (1997) suggested that the highly skewed X-inactivation pattern of the grandmother indicated that her NDI phenotype was caused by dominant methylation of the normal allele of the AVPR2 gene. Carroll et al. (2006) described evidence of skewed X inactivation associated with a novel deletion in the AVPR2 gene.
Bode and Crawford (1969) and Bode and Miettinen (1970) proposed that patients with nephrogenic diabetes insipidus in eastern North America shared a common ancestor, an Ulster Scot who had arrived in Halifax in 1761 on the ship Hopewell. ... Bode and Crawford (1969) and Bode and Miettinen (1970) proposed that patients with nephrogenic diabetes insipidus in eastern North America shared a common ancestor, an Ulster Scot who had arrived in Halifax in 1761 on the ship Hopewell. They also suggested a link between this family and the large Mormon pedigree reported by Cannon (1955). Bode and Crawford (1969) stated that 'it is likely that the Hopewell hypothesis can never be proved.' However, Bichet et al. (1992) used haplotype analysis to show that there was not likely to be a connection between the family reported by Cannon (1955) and the Hopewell kindred. Genealogical studies also seemed to exclude a connection. Bichet et al. (1992) also studied 11 other affected families of diverse ethnic backgrounds: 5 French Canadian, 1 African American, 1 Puerto Rican, 1 Iranian, 2 French, and 1 English. All of the families had similar phenotypic features and showed linkage to markers in the Xq28 region. Differences in RFLP patterns indicated that the 'Hopewell hypothesis' could not explain the origin of NDI in many of the North American families. Holtzman et al. (1993) identified the AVPR2 mutation in the Hopewell family (W71X; 300358.0008). This finding and data on various other mutations in the AVPR2 gene found in North American pedigrees, both of Ulster Scot ancestry and others, made the founder effect as proposed in the Hopewell hypothesis invalid. Bichet et al. (1993) likewise presented evidence for multiple mutations in the AVPR2 gene, arguing against the Hopewell founder hypothesis.