Detection of skewed X-inactivation in two female carriers of vasopressin type 2 receptor gene mutation

Abstract

Most cases of congenital nephrogenic diabetes insipidus (NDI) are inherited in an X-linked manner, which is due to the mutations of the vasopressin type 2 receptor (V2R) gene. However, recent reports have presented female NDI patients with heterozygote V2R gene mutations. The mechanism of inheritance was thought to be skewed X-inactivation. We present a family with congenital NDI. Three male members were diagnosed with NDI, and examination of their V2R gene revealed a G inserted at nucleotide 804 of the open reading frame. Three female individuals display different degrees of symptoms of NDI, and all of them possess both the normal and abnormal genes. The X-inactivation patterns of the female members were investigated via the detection of methylated trinucleotide repeat in the human androgen receptor gene. The grandmother showed extremely skewed methylation of one X chromosome, and the mother revealed moderately skewed methylation. The daughter of the grandmother's sister, who has no symptoms of NDI, showed random methylation. The highly skewed X-inactivation pattern of the grandmother suggests that her NDI phenotype is caused by dominant methylation of the normal allele of V2R gene.