NATURE AND RECURRENCE OF AVPR2 MUTATIONS IN X-LINKED NEPHROGENIC DIABETES-INSIPIDUS

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease with d efective renal and extrarenal arginine-vasopressin V-2 receptor respon ses due to mutations in the AVPR2 gene in Xq28. We analyzed 31 indepen dent NDI families to determine the nature and recurrence of AVPR2 muta tions. Twenty-one new putative disease-causing mutations were identifi ed: 113delCT, 253del35, 255del9, 274insG, V88M, R106C, 402delCT, C112R , Y124X, S126F, W164S, S167L, 684delTA, 804insG, W284X, A285P, W293X, R337X, and three large deletions or gene rearrangements. Five other mu tations-R113W, Y128S, R137H, R181C, and R202C-that previously had been reported in other families were detected. There was evidence for recu rrent mutation for four mutations (R113W, R137H, S167L, and R337X). Ei ght de novo mutation events were detected (274insG, R106C, Y128S, 167L [twice], R202C, 684delTA, and R337X). The origins were maternal (one) , grandmaternal (one), and grandpaternal (six). In the 31 NDI families and 6 families previously reported by us, there is evidence both for mutation hot spots for nucleotide substitutions and for small deletion s and insertions. More than half (58%) of the nucleotide substitutions in 26 families could be a consequence of 5-methyl-cytosine deaminatio n at a CpG dinucleotide. Most of the small deletions and insertions co uld be attributed to slipped mispairing during DNA replication.