DETECTION OF SKEWED X-INACTIVATION IN 2 FEMALE CARRIERS OF VASOPRESSIN TYPE-2 RECEPTOR GENE MUTATION

Most cases of congenital nephrogenic diabetes insipidus (NDI) are inhe rited in an X-Linked manner, which is due to the mutations of the vaso pressin type 2 receptor (V2R) gene. However, recent reports have prese nted female NDI patients with heterozygote V2R gene mutations. The mec hanism of inheritance was thought to be skewed X-inactivation. We pres ent a family with congenital NDI. Three male members were diagnosed wi th NDI, and examination of their V2R gene revealed a G inserted at nuc leotide 804 of the open reading frame. Three female individuals displa y different degrees of symptoms of NDI, and all of them possess both t he normal and abnormal genes. The X-inactivation patterns of the femal e members were investigated via the detection of methylated trinucleot ide repeat in the human androgen receptor gene. The grandmother showed extremely skewed methylation of one X chromosome, and the mother reve aled moderately skewed methylation. The daughter of the grandmother's sister, who has no symptoms of NDI, showed random methylation. The hig hly skewed X-inactivation pattern of the grandmother suggests that her NDI phenotype is caused by dominant methylation of the normal allele of V2R gene.