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A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance.
J Clin Endocrinol Metab. 2008 Mar; 93(3):661-5.JC

Abstract

CONTEXT

Pseudohypoparathyroidism (PHP) type Ia is a rare maternally transmitted disease due to maternal loss-of-function mutations of GNAS, the gene encoding Galphas, the alpha-stimulatory subunit of the G protein. Affected individuals display hormonal resistance (mainly PTH and TSH resistance) and Albright hereditary osteodystrophy. PHP type Ib (PHP-Ib), usually defined by isolated renal resistance to PTH and sometimes mild TSH resistance, is due to a maternal loss of GNAS exon A/B methylation, leading to decreased Galphas expression in specific tissues.

OBJECTIVE AND RESULTS

We report a girl with obvious Albright osteodystrophy features, PTH resistance, normal Galphas bioactivity in red blood cells, yet no loss-of-function mutation in the GNAS coding sequence (exons 1-13). The methylation analysis of the four GNAS differentially methylated regions, i.e. NESP, AS, XL, and A/B, revealed broad methylation changes at all differentially methylated regions, including GNAS exon A/B, leading to a paternal epigenotype on both alleles.

CONCLUSIONS

This observation suggests that: 1) the decreased expression of Galphas due to GNAS epimutations is not restricted to the renal tubule but may affect nonimprinted tissues like bone; 2) PHP-Ib is a heterogeneous disorder that should lead to studying GNAS epigenotype in patients with PHP and no mutation in GNAS exons 1-13, regardless of their physical features.

Authors+Show Affiliations

Pediatric Endocrinology and Institut National de la Santé et de la Recherche Médicale U561, Hôpital St-Vincent de Paul, 82 avenue Denfert-Rochereau, 75014 Paris V University, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18182455

Citation

Mariot, Virginie, et al. "A Maternal Epimutation of GNAS Leads to Albright Osteodystrophy and Parathyroid Hormone Resistance." The Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 3, 2008, pp. 661-5.
Mariot V, Maupetit-Méhouas S, Sinding C, et al. A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. J Clin Endocrinol Metab. 2008;93(3):661-5.
Mariot, V., Maupetit-Méhouas, S., Sinding, C., Kottler, M. L., & Linglart, A. (2008). A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. The Journal of Clinical Endocrinology and Metabolism, 93(3), 661-5. https://doi.org/10.1210/jc.2007-0927
Mariot V, et al. A Maternal Epimutation of GNAS Leads to Albright Osteodystrophy and Parathyroid Hormone Resistance. J Clin Endocrinol Metab. 2008;93(3):661-5. PubMed PMID: 18182455.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. AU - Mariot,Virginie, AU - Maupetit-Méhouas,Stéphanie, AU - Sinding,Christiane, AU - Kottler,Marie-Laure, AU - Linglart,Agnès, Y1 - 2008/01/08/ PY - 2008/1/10/pubmed PY - 2008/4/16/medline PY - 2008/1/10/entrez SP - 661 EP - 5 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 93 IS - 3 N2 - CONTEXT: Pseudohypoparathyroidism (PHP) type Ia is a rare maternally transmitted disease due to maternal loss-of-function mutations of GNAS, the gene encoding Galphas, the alpha-stimulatory subunit of the G protein. Affected individuals display hormonal resistance (mainly PTH and TSH resistance) and Albright hereditary osteodystrophy. PHP type Ib (PHP-Ib), usually defined by isolated renal resistance to PTH and sometimes mild TSH resistance, is due to a maternal loss of GNAS exon A/B methylation, leading to decreased Galphas expression in specific tissues. OBJECTIVE AND RESULTS: We report a girl with obvious Albright osteodystrophy features, PTH resistance, normal Galphas bioactivity in red blood cells, yet no loss-of-function mutation in the GNAS coding sequence (exons 1-13). The methylation analysis of the four GNAS differentially methylated regions, i.e. NESP, AS, XL, and A/B, revealed broad methylation changes at all differentially methylated regions, including GNAS exon A/B, leading to a paternal epigenotype on both alleles. CONCLUSIONS: This observation suggests that: 1) the decreased expression of Galphas due to GNAS epimutations is not restricted to the renal tubule but may affect nonimprinted tissues like bone; 2) PHP-Ib is a heterogeneous disorder that should lead to studying GNAS epigenotype in patients with PHP and no mutation in GNAS exons 1-13, regardless of their physical features. SN - 0021-972X UR - https://www.unboundmedicine.com/medline/citation/18182455/A_maternal_epimutation_of_GNAS_leads_to_Albright_osteodystrophy_and_parathyroid_hormone_resistance_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2007-0927 DB - PRIME DP - Unbound Medicine ER -