Completely skewed X-inactivation in a mentally retarded young female with pseudohypoparathyroidism type IB and juvenile renin-dependent hypertension

Abstract

Genetic analysis of the GNAS gene was performed in a patient with idiopathic renin-dependent hypertension, PTH resistance, and Albright's hereditary osteodystrophy-like characteristics such as a round face, short stature, obesity, and mental retardation (IQ, 49). Mutational analysis showed no mutations in exons 1-13 or in any exon-intron boundary. However, methylation-status analysis revealed a bialleic methylation defect in GNAS exon 1A, indicating that a GNAS- imprinting defect is the cause of her PTH resistance, as commonly observed in pseudohypoparathyroidism type IB. The imprinting defect, however, could not explain her renin-dependent hypertension and Albright's hereditary osteodystrophy-like phenotype. There are many types of X-linked mental retardation. Syndromic X-linked mental retardation, such as X-linked α-thalassemia mental retardation syndrome and Rett syndrome, is reportedly associated with abnormal imprinting. To further investigate this unexplained phenotype, we tested whether this patient showed skewed X-inactivation (SXI) presumably as a result of postinactivation selection against cells with a mutated gene on the active X-chromosome. Completely SXI was observed in the DNA from her leukocytes, urinary sediment, and renal tissue. A mutation of the X-chromosome might be correlated with this phenotype because of a close association between completely SXI and X-chromosomal mutation.