Gsα activity is reduced in erythrocyte membranes of patients with psedohypoparathyroidism due to epigenetic alterations at the GNAS locus

• Published in: Journal of bone and mineral research Vol. 26; no. 8; pp. 1864 - 1870
• Main Authors: Zazo, Celia, Thiele, Susanne, Martín, Cesar, Fernandez‐Rebollo, Eduardo, Martinez‐Indart, Lorea, Werner, Ralf, Garin, Intza, Group, Spanish PHP, Hiort, Olaf, Perez de Nanclares, Guiomar
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-08-2011; Wiley
• Subjects: Adolescent; Adult; AHO PHENOTYPE; Biological and medical sciences; Child; Child, Preschool; Chromogranins; Epigenesis, Genetic; Erythrocyte Membrane - metabolism; Female; Fundamental and applied biological sciences. Psychology; Genetic Loci - genetics; GNAS; Gsα PROTEIN; GTP-Binding Protein alpha Subunits, Gs - genetics; Humans; Immunoblotting; Infant; Male; METHYLATION DEFECTS; Mutation - genetics; PSEUDOHYPOPARATHYROIDISM; Pseudohypoparathyroidism - genetics; Skeleton and joints; Vertebrates: osteoarticular system, musculoskeletal system; Young Adult; Endocrinopathy; Human; Gsα PROTEIN; Red blood cell; AHO PHENOTYPE; Protein; Genetic disease; Osteoarticular system; Blood cell; Vertebrata; Phenotype; Mammalia; Pseudohypoparathyroidism; GNAS; Locus; Methylation; METHYLATION DEFECTS
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.369

In pseudohypoparathyroidism (PHP), PTH resistance results from impairment of signal transduction of G protein–coupled receptors caused by a deficiency of the Gsα‐cAMP signaling cascade due to diminished Gsα activity in maternally imprinted tissues. In PHP‐Ia, inactivating mutations of the GNAS gene lead to haploinsufficiency in some tissues with biallelic expression, so in addition to PHP, Albright's hereditary osteodystrophy (AHO) is also present. In PHP‐Ib, caused by methylation defects at the GNAS locus, diminished Gsα activity was thought to be limited to maternally imprinted tissues, such as the renal proximal tubule and the thyroid, leading to a lack of AHO. Recently, we demonstrated methylation defects in patients with AHO signs, indicating a connection between epigenetic changes and AHO. Our objective was to determine Gsα activity in erythrocyte membranes in patients with epigenetic defects at the GNAS locus compared to normal controls and patients with inactivating GNAS mutations. Gsα activity and expression, mutation of the GNAS locus, and methylation status were studied in patients with PHP and mild signs of AHO (PHP‐Ia: 12; PHP‐Ib: 17, of which 8 had some features of AHO). Then, we statistically compared the Gsα activity of the different PHP subtypes. Patients with methylation defects at the GNAS locus show a significant decrease in erythrocyte Gsα activity compared to normal controls (PHP‐Ib versus controls, p < .001). This was significantly lower in patients with AHO signs (PHP‐Ib + mild‐AHO versus PHP‐Ib, p < .05). Our research shows that PHP‐Ia and PHP‐Ib classification is not only overlapped genetically, as reported, but also in terms of Gsα activity. Reduced expression of GNAS due to methylation defects could downregulate Gsα activity in other tissues beyond those described and could also be causative of AHO. © 2011 American Society for Bone and Mineral Research