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Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of albright hereditary osteodystrophy and molecular analysis in 40 patients.
J Clin Endocrinol Metab 2010; 95(2):651-8JC

Abstract

CONTEXT

The two main subtypes of pseudohypoparathyroidism (PHP), PHP-Ia and -Ib, are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward PTH and additional hormones, whereas PHP-Ib patients do not have AHO, and hormone resistance appears to be limited to PTH and TSH. Recently, methylation defects have been detected in few patients with PHP and mild AHO, indicating a molecular overlap between the two forms.

OBJECTIVES

The aim of the study was to screen patients with clinically diagnosed PHP-Ia for methylation defects and to investigate the presence of correlations between the molecular findings and AHO severity.

PATIENTS AND METHODS

We investigated differential methylation of GNAS regions and STX16 microdeletions in genomic DNA from 40 patients with sporadic AHO and multihormone resistance, with no mutations in Gsalpha-coding GNAS exons.

RESULTS

Molecular analysis showed GNAS cluster imprinting defects in 24 of the 40 patients analyzed. No STX16 deletion was detected. The presence of imprinting defects was not associated with the severity of AHO or with specific AHO signs.

CONCLUSIONS

We report the largest series of the literature of patients with clinical AHO and multihormone resistance and no mutation in the Gsalpha gene. Our findings of frequent GNAS imprinting defects further confirm the existence of an overlap between molecular and clinical features of PHP-Ia and PHP-Ib and highlight the necessity of a new clinical classification of the disease that takes into account the recent knowledge on the molecular basis underlying these defects.

Authors+Show Affiliations

Unità di Endocrinologia, Padiglione Granelli, Fondazione Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico, Via Francesco Sforza, 35, 20122 Milano, Italy. giovanna.mantovani@unimi.itNo 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)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20061437

Citation

Mantovani, Giovanna, et al. "Pseudohypoparathyroidism and GNAS Epigenetic Defects: Clinical Evaluation of Albright Hereditary Osteodystrophy and Molecular Analysis in 40 Patients." The Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 2, 2010, pp. 651-8.
Mantovani G, de Sanctis L, Barbieri AM, et al. Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab. 2010;95(2):651-8.
Mantovani, G., de Sanctis, L., Barbieri, A. M., Elli, F. M., Bollati, V., Vaira, V., ... Spada, A. (2010). Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of albright hereditary osteodystrophy and molecular analysis in 40 patients. The Journal of Clinical Endocrinology and Metabolism, 95(2), pp. 651-8. doi:10.1210/jc.2009-0176.
Mantovani G, et al. Pseudohypoparathyroidism and GNAS Epigenetic Defects: Clinical Evaluation of Albright Hereditary Osteodystrophy and Molecular Analysis in 40 Patients. J Clin Endocrinol Metab. 2010;95(2):651-8. PubMed PMID: 20061437.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of albright hereditary osteodystrophy and molecular analysis in 40 patients. AU - Mantovani,Giovanna, AU - de Sanctis,Luisa, AU - Barbieri,Anna Maria, AU - Elli,Francesca M, AU - Bollati,Valentina, AU - Vaira,Valentina, AU - Labarile,Pamela, AU - Bondioni,Sara, AU - Peverelli,Erika, AU - Lania,Andrea G, AU - Beck-Peccoz,Paolo, AU - Spada,Anna, Y1 - 2010/01/08/ PY - 2010/1/12/entrez PY - 2010/1/12/pubmed PY - 2010/3/3/medline SP - 651 EP - 8 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 95 IS - 2 N2 - CONTEXT: The two main subtypes of pseudohypoparathyroidism (PHP), PHP-Ia and -Ib, are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward PTH and additional hormones, whereas PHP-Ib patients do not have AHO, and hormone resistance appears to be limited to PTH and TSH. Recently, methylation defects have been detected in few patients with PHP and mild AHO, indicating a molecular overlap between the two forms. OBJECTIVES: The aim of the study was to screen patients with clinically diagnosed PHP-Ia for methylation defects and to investigate the presence of correlations between the molecular findings and AHO severity. PATIENTS AND METHODS: We investigated differential methylation of GNAS regions and STX16 microdeletions in genomic DNA from 40 patients with sporadic AHO and multihormone resistance, with no mutations in Gsalpha-coding GNAS exons. RESULTS: Molecular analysis showed GNAS cluster imprinting defects in 24 of the 40 patients analyzed. No STX16 deletion was detected. The presence of imprinting defects was not associated with the severity of AHO or with specific AHO signs. CONCLUSIONS: We report the largest series of the literature of patients with clinical AHO and multihormone resistance and no mutation in the Gsalpha gene. Our findings of frequent GNAS imprinting defects further confirm the existence of an overlap between molecular and clinical features of PHP-Ia and PHP-Ib and highlight the necessity of a new clinical classification of the disease that takes into account the recent knowledge on the molecular basis underlying these defects. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/20061437/Pseudohypoparathyroidism_and_GNAS_epigenetic_defects:_clinical_evaluation_of_albright_hereditary_osteodystrophy_and_molecular_analysis_in_40_patients_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2009-0176 DB - PRIME DP - Unbound Medicine ER -