AVPR2 variants and mutations in nephrogenic diabetes insipidus: Review and missense mutation significance

Abstract

Almost 90% of nephrogenic diabetes insipidus (NDI) is due to mutations in the arginine-vasopressin receptor 2 gene (AVPR2). We retrospectively examined all the published mutations/variants in AVPR2. We planned to perform a comprehensive review of all the AVPR2 mutations/variants and to test whether any amino acid change causing a missense mutation is significantly more or less common than others. We performed a Medline search and collected detailed information regarding all AVPR2 mutations and variants. We performed a frequency comparison between mutated and wild-type amino acids and codons. We predicted the mutation effect or reported it based on published in vitro studies. We also reported the ethnicity of each mutation/variant carrier. In summary, we identified 211 AVPR2 mutations which cause NDI in 326 families and 21 variants which do not cause NDI in 71 NDI families. We described 15 different types of mutations including missense, frameshift, inframe deletion, deletion, insertion, nonsense, duplication, splicing and combined mutations. The missense mutations represent the 55.83% of all the NDI published families. Arginine and tyrosine are significantly (P = 4.07E-08 and P = 3.27E-04, respectively) the AVPR2 most commonly mutated amino acids. Alanine and glutamate are significantly (P = 0.009 and P = 0.019, respectively) the least mutated AVPR2 amino acids. The spectrum of mutations varies from rare gene variants or polymorphisms not causing NDI to rare mutations causing NDI, among which arginine and tyrosine are the most common missense. The AVPR2 mutations are spread world-wide. Our study may serve as an updated review, comprehensive of all AVPR2 variants and specific gene locations. J. Cell. Physiol. 217: 605-617, 2008. (c) 2008 Wiley-Liss, Inc.

Hereditary nephrogenic diabetes insipidus in Japanese patients: analysis of 78 families and report of 22 new mutations in AVPR2 and AQP2

“…Splicing mutations were the least common. This relative frequency of disease-causing AVPR2 mutations is consistent with the results of a worldwide summary of AVPR2 mutations, as shown in Table 2 [19], again confirming that the genetic mechanisms causing NDI are the same in different ethnic groups [19]. Of these AVPR2 mutations, 19 mutations were novel, and the other mutations were previously reported or recurrences of the previously reported mutations.…”

“…More than 220 disease-causing mutations have been reported for AVPR2 [19], and 50 disease-causing mutations have been reported for AQP2 [7,20]. Our present report of 22 new putatively disease-causing mutations significantly increases the numbers of known NDI-causing mutations by about 10 %.…”

“…Table 2 summarizes the types of AVPR2 mutations. Gene variants/ polymorphisms that have been reported not to cause NDI [19] were excluded in this summary. Missense mutations were most common, accounting for half of the mutations, followed by deletion mutations, insertion mutations, and nonsense mutations.…”

“…The index subject was heterozygous for this mutation. The codon Asp85 seems functionally important, because another missense mutation on this residue, D85N, was reportedly causative in six families [19]. L90P was observed in two unrelated families.…”

“…L131P were found in two young brothers with complete NDI, and their mother was a heterozygous carrier of the mutation with no NDI symptoms. Mutation on Leu131 has not been reported, but missense mutations on encompassing residues, I130L, I130F and A132D have been shown to be causative [19], indicating that this region is functionally important. W164R was found in a boy with NDI, and his mother was a heterozygous carrier of the mutation.…”