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Completely Skewed X-Inactivation in a Mentally Retarded Young Female with Pseudohypoparathyroidism Type IB and Juvenile Renin-Dependent Hypertension

Second Department of Internal Medicine, School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan

Address all correspondence and requests for reprints to: Masashi Demura, M.D., 13-1 Takara-machi, Kanazawa 920-8640, Japan. E-mail: fu21i8n3{at}sr.incl.ne.jp.

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 -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.

Abbreviations: AHO, Albright’s hereditary osteodystrophy; AR, androgen receptor; CT, computed tomography; MSP, methylation-specific PCR; PAC, plasma aldosterone concentration; PHP, pseudohypoparathyroidism; PHPIA, PHP type IA; PHPIB, PHP type IB; PRA, plasma-renin activity; SXI, skewed X-inactivation; XLMR, X-linked mental retardation.

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