TY - JOUR
T1 - Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy
AU - De Nanclares, Guiomar Pérez
AU - Fernández-Rebollo, Eduardo
AU - Santin, Izortze
AU - García-Cuartero, Beatriz
AU - Gaztambide, Sonia
AU - Menéndez, Edelmiro
AU - Morales, Maria Jose
AU - Pombo, Manuel
AU - Bilbao, José Ramón
AU - Barros, Francisco
AU - Zazo, Nuria
AU - Ahrens, Wiebke
AU - Jüppner, Harald
AU - Hiort, Olaf
AU - Castaño, Luis
AU - Bastepe, Murat
N1 - Funding Information:
This work was partially supported by Grant RCMN (C03/08) from the Instituto de Salud Carlos III, Madrid, Spain; a grant from Pfizer Laboratories; grants from the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (RO1 46718-10 to H.J. and KO1 DK-062973 to M.B.); and a grant from the Bundesministerium für Bildung und Forschung (German Ministry for Research and Education; GFGM01141901 to W.A. and O.H.). G.P.d.N. and J.R.B. are FIS Research Scientists supported by the Spanish Ministry of Health (Fellowship 03/0064 and 99/3076, respectively).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2007/6
Y1 - 2007/6
N2 - Context: Several endocrine disorders that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). PHP type I, associated with blunted PTH-induced nephrogenous cAMP formation and phosphate excretion, is subdivided according to the presence or absence of additional endocrine abnormalities, Albright's hereditary osteodystrophy (AHO), and reduced Gsα activity caused by GNAS mutations. Objective: We sought to identify the molecular defect in four unrelated patients who were thought to have PHP-Ia because of PTH and TSH resistance and mild AHO features. Methods: Gsα activity and mutation analysis, and assessment of GNAS haplotype, methylation, and gene expression were performed for probands and family members. Results: Two patients showed modest decreases in erythrocyte Gsα activity. Instead of Gsα point mutations, however, all four patients showed methylation defects of the GNAS locus, a feature previously described only for PHP-Ib. Furthermore, one patient with an isolated loss of GNAS exon A/B methylation had the 3-kb STX16 deletion frequently identified in PHP-Ib patients. In all but one of the remaining patients, haplotype analysis excluded large deletions or uniparental disomy as the cause of the observed methylation changes. Conclusions: Our investigations indicate that an overlap may exist between molecular and clinical features of PHP-Ia and PHP-Ib. No current mechanisms can explain the AHO-like features of our patients, some of which may not be linked to GNAS. Therefore, patients with hormone resistance and AHO-like features in whom coding Gsα mutations have been excluded should be evaluated for epigenetic alterations within GNAS.
AB - Context: Several endocrine disorders that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). PHP type I, associated with blunted PTH-induced nephrogenous cAMP formation and phosphate excretion, is subdivided according to the presence or absence of additional endocrine abnormalities, Albright's hereditary osteodystrophy (AHO), and reduced Gsα activity caused by GNAS mutations. Objective: We sought to identify the molecular defect in four unrelated patients who were thought to have PHP-Ia because of PTH and TSH resistance and mild AHO features. Methods: Gsα activity and mutation analysis, and assessment of GNAS haplotype, methylation, and gene expression were performed for probands and family members. Results: Two patients showed modest decreases in erythrocyte Gsα activity. Instead of Gsα point mutations, however, all four patients showed methylation defects of the GNAS locus, a feature previously described only for PHP-Ib. Furthermore, one patient with an isolated loss of GNAS exon A/B methylation had the 3-kb STX16 deletion frequently identified in PHP-Ib patients. In all but one of the remaining patients, haplotype analysis excluded large deletions or uniparental disomy as the cause of the observed methylation changes. Conclusions: Our investigations indicate that an overlap may exist between molecular and clinical features of PHP-Ia and PHP-Ib. No current mechanisms can explain the AHO-like features of our patients, some of which may not be linked to GNAS. Therefore, patients with hormone resistance and AHO-like features in whom coding Gsα mutations have been excluded should be evaluated for epigenetic alterations within GNAS.
UR - http://www.scopus.com/inward/record.url?scp=34347217115&partnerID=8YFLogxK
U2 - 10.1210/jc.2006-2287
DO - 10.1210/jc.2006-2287
M3 - Journal articles
C2 - 17405843
AN - SCOPUS:34347217115
SN - 0021-972X
VL - 92
SP - 2370
EP - 2373
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 6
ER -