van Lieburg AF et al. (1994), Patients with autosomal nephrogenic diabetes in...

XB-ART-20777

Am J Hum Genet 1994 Oct 01;554:648-52.

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Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene.

van Lieburg AF , Verdijk MA , Knoers VV , van Essen AJ , Proesmans W , Mallmann R , Monnens LA , van Oost BA , van Os CH , Deen PM .

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Mutations in the X-chromosomal V2 receptor gene are known to cause nephrogenic diabetes insipidus (NDI). Besides the X-linked form, an autosomal mode of inheritance has been described. Recently, mutations in the autosomal gene coding for water-channel aquaporin 2 (AQP2) of the renal collecting duct were reported in an NDI patient. In the present study, missense mutations and a single nucleotide deletion in the aquaporin 2 gene of three NDI patients from consanguineous matings are described. Expression studies in Xenopus oocytes showed that the missense AQP2 proteins are nonfunctional. These results prove that mutations in the AQP2 gene cause autosomal recessive NDI.

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Species referenced: Xenopus
Genes referenced: aqp2

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	Figure I del/i del/del del/i P3 Pedigrees of the 3 NDI-families. Blackened symbols de note affected individuals; hatched symbols denote that NDI is suspected; and symbols with diagonal slashes through them denote deceased indi viduals. Presence of the mutant alleles is depicted by the relevant amino acid substitution (R187C or G64R) or single nucleotide deletion (del); and normal alleles are denoted by a plus sign.
	Figure 2 Human AQP2 cDNA gene sequence and deduced amino acid sequence. Nucleotide numbering of AQP2 starts at the initi ation site of translation. Exon and intron sequences are depicted by up percase and lowercase characters, respectively. Flanking intron sequences are separated by dots. The nucleotides mutated in the AQP2 genes of the patients are indicated above the DNA sequence: V = CSS9 changed to T in patient 1; A = G190 changed to A in patient 2; and A = C369 deletion in patient 3. The genomic sequence is deposited in GenBank under ac cession number Z29491.
	Figure 3 Proposed topology of the AQP2 protein. The positions of the single nucleotide deletion and amino acid substitutions found in the patients are indicated by arrows. The amino acid residues that are conserved within the MIP family are indicated by blackened symbols.
	Figure 4 Pf of Xenopus oocytes injected with cRNAs encoding wild-type AQP2 and/or AQP2 harboring the substitution of arginine 64 for glycine (G64R). Mean and SEM values of at least 10 oocytes are shown.