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Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy.
J Clin Endocrinol Metab. 2007 Jun; 92(6):2370-3.JC

Abstract

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 Gsalpha 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

Gsalpha 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 Gsalpha activity. Instead of Gsalpha 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 Gsalpha mutations have been excluded should be evaluated for epigenetic alterations within GNAS.

Authors+Show Affiliations

Endocrinology and Diabetes Research Group, Hospital de Cruces, Cruces-Barakaldo E48903 Bizkaia, Basque Country, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17405843

Citation

de Nanclares, Guiomar Pérez, et al. "Epigenetic Defects of GNAS in Patients With Pseudohypoparathyroidism and Mild Features of Albright's Hereditary Osteodystrophy." The Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 6, 2007, pp. 2370-3.
de Nanclares GP, Fernández-Rebollo E, Santin I, et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy. J Clin Endocrinol Metab. 2007;92(6):2370-3.
de Nanclares, G. P., Fernández-Rebollo, E., Santin, I., García-Cuartero, B., Gaztambide, S., Menéndez, E., Morales, M. J., Pombo, M., Bilbao, J. R., Barros, F., Zazo, N., Ahrens, W., Jüppner, H., Hiort, O., Castaño, L., & Bastepe, M. (2007). Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy. The Journal of Clinical Endocrinology and Metabolism, 92(6), 2370-3.
de Nanclares GP, et al. Epigenetic Defects of GNAS in Patients With Pseudohypoparathyroidism and Mild Features of Albright's Hereditary Osteodystrophy. J Clin Endocrinol Metab. 2007;92(6):2370-3. PubMed PMID: 17405843.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2007/04/03/ PY - 2007/4/5/pubmed PY - 2007/7/19/medline PY - 2007/4/5/entrez SP - 2370 EP - 3 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 92 IS - 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 Gsalpha 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: Gsalpha 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 Gsalpha activity. Instead of Gsalpha 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 Gsalpha mutations have been excluded should be evaluated for epigenetic alterations within GNAS. SN - 0021-972X UR - https://www.unboundmedicine.com/medline/citation/17405843/Epigenetic_defects_of_GNAS_in_patients_with_pseudohypoparathyroidism_and_mild_features_of_Albright's_hereditary_osteodystrophy_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2006-2287 DB - PRIME DP - Unbound Medicine ER -