Completely skewed X-inactivation in a mentally retarded young female with pseudohypoparathyroidism type IB and juvenile renin-dependent hypertension.
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 alpha-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.
Demura
Masashi
M
Second Department of Internal Medicine, School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan. fu21i8n3@sr.incl.ne.jp
Takeda
Yoshiyu
Y
Yoneda
Takashi
T
Furukawa
Kenji
K
Tachi
Aiko
A
Mabuchi
Hiroshi
H
D000328:Adult; D002864:Chromogranins; D041321:Chromosomes, Human, X; D019175:DNA Methylation; D004303:Dosage Compensation, Genetic; D005091:Exons; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D020962:Heterotrimeric GTP-Binding Proteins; D006801:Humans; D006977:Hypertension, Renal / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics*; D009419:Nerve Tissue Proteins; D010641:Phenotype; D021122:Protein Subunits / Q000235:genetics; D011547:Pseudohypoparathyroidism / Q000150:complications / Q000235:genetics* / Q000473:pathology; D012083:Renin / Q000378:metabolism; D018911:Trinucleotide Repeats
D002864:Chromogranins; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D012083:Renin; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins