A novel disease-causing mutation in AVPR2: Q96H

Abstract

A 4-month-old male infant was diagnosed with nephrogenic diabetes insipidus (NDI). Genetic testing of the arginine vasopressin receptor-2 (AVPR2) yielded a novel X-linked mutation, termed Q96H, in both the propositus and his mother; there was no family history. Protein sequence comparison between AVPR subtypes shows that Q96 is part of a highly conserved motif. Many other disease-causing mutations, confirmed with in vitro expression studies, map to surrounding residues. Molecular modelling studies showed that the equivalent residue in AVPR1 is likely critical for vasopressin binding. We posit that Q96 must be important for the integrity of AVPR2 function.

Keywords: AVPR2; DDAVP; nephrogenic diabetes insipidus; vasopressin.

Fig. 1

(a) Family tree of the proband (indicated by an arrow). (b) DNA chromatogram of the affected proband and his mother, who is a carrier of the mutated (GTG) allele (the normal amino acid is CTG).

Fig. 2

(a) Schematic representation of AVPR2 modified from Bichet [3] to include the new mutation Q96H (arrow). Please see http://www. medicine.mcgill.ca/nephros for a list of mutations. (b) Sequence homology in TM-2 (and flanking regions) of various AVPR subtypes in human, mouse and rat. The novel mutation (located at residue Q96, dotted arrow) is part of one of the largest and most extensively conserved areas amongst the various proteins of this family. Disease-causing mutations in AVPR2 have been reported in the residues highlighted at the bottom. Thick arrows indicate mutations in highly conserved regions, thin arrows in less conserved areas and squared arrows refer to regions with poor homology. Sequence accession numbers, in descending order: P37288.1, Q62463.1, P30560.4, Q9WU02.1, P30518.1, O88721.1 and Q00788.2. Sequences were aligned using the software Geneious Pro 3.5.6 (www.geneious.com); residue numbering is based on Homo sapiens AVPR2.