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Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development.
J Clin Endocrinol Metab 2013; 98(9):E1549-56JC

Abstract

CONTEXT

Heterozygous GNAS inactivating mutations cause pseudohypoparathyroidism type Ia (PHP-Ia) when maternally inherited and pseudopseudohypoparathyroidism (PPHP)/progressive osseous heteroplasia (POH) when paternally inherited. Recent studies have suggested that mutations on the paternal, but not the maternal, GNAS allele could be associated with intrauterine growth retardation (IUGR) and thus small size for gestational age.

OBJECTIVES

The aim of the study was to confirm and expand these findings in a large number of patients presenting with either PHP-Ia or PPHP/POH.

PATIENTS AND METHODS

We collected birth parameters (ie, gestational age, weight, length, and head circumference) of patients with either PHP-Ia (n = 29) or PPHP/POH (n = 26) with verified GNAS mutations. The parental allele carrying the mutation was assessed by investigating the parents or, when a de novo mutation was identified, through informative intragenic polymorphisms.

RESULTS

Heterozygous GNAS mutations on either parental allele were associated with IUGR. However, when these mutations are located on the paternal GNAS allele, IUGR was considerably more pronounced than with mutations on the maternal allele. Moreover, birth weights were lower with paternal GNAS mutations affecting exons 2-13 than with exon 1/intron 1 mutations.

CONCLUSIONS

These data indicate that a paternally derived GNAS transcript, possibly XLαs, is required for normal fetal growth and development and that this transcript affects placental functions. Thus, similar to other imprinted genes, GNAS controls growth and/or fetal development.

Authors+Show Affiliations

Centre Hospitalier Universitaire de Caen, Department of Genetics, Reference Centre for Rare Disorders of Calcium and Phosphorus Metabolism, F-14000 Caen, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

23884777

Citation

Richard, Nicolas, et al. "Paternal GNAS Mutations Lead to Severe Intrauterine Growth Retardation (IUGR) and Provide Evidence for a Role of XLαs in Fetal Development." The Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 9, 2013, pp. E1549-56.
Richard N, Molin A, Coudray N, et al. Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development. J Clin Endocrinol Metab. 2013;98(9):E1549-56.
Richard, N., Molin, A., Coudray, N., Rault-Guillaume, P., Jüppner, H., & Kottler, M. L. (2013). Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development. The Journal of Clinical Endocrinology and Metabolism, 98(9), pp. E1549-56. doi:10.1210/jc.2013-1667.
Richard N, et al. Paternal GNAS Mutations Lead to Severe Intrauterine Growth Retardation (IUGR) and Provide Evidence for a Role of XLαs in Fetal Development. J Clin Endocrinol Metab. 2013;98(9):E1549-56. PubMed PMID: 23884777.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development. AU - Richard,Nicolas, AU - Molin,Arnaud, AU - Coudray,Nadia, AU - Rault-Guillaume,Pauline, AU - Jüppner,Harald, AU - Kottler,Marie-Laure, Y1 - 2013/07/24/ PY - 2013/7/26/entrez PY - 2013/7/26/pubmed PY - 2013/11/10/medline SP - E1549 EP - 56 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 98 IS - 9 N2 - CONTEXT: Heterozygous GNAS inactivating mutations cause pseudohypoparathyroidism type Ia (PHP-Ia) when maternally inherited and pseudopseudohypoparathyroidism (PPHP)/progressive osseous heteroplasia (POH) when paternally inherited. Recent studies have suggested that mutations on the paternal, but not the maternal, GNAS allele could be associated with intrauterine growth retardation (IUGR) and thus small size for gestational age. OBJECTIVES: The aim of the study was to confirm and expand these findings in a large number of patients presenting with either PHP-Ia or PPHP/POH. PATIENTS AND METHODS: We collected birth parameters (ie, gestational age, weight, length, and head circumference) of patients with either PHP-Ia (n = 29) or PPHP/POH (n = 26) with verified GNAS mutations. The parental allele carrying the mutation was assessed by investigating the parents or, when a de novo mutation was identified, through informative intragenic polymorphisms. RESULTS: Heterozygous GNAS mutations on either parental allele were associated with IUGR. However, when these mutations are located on the paternal GNAS allele, IUGR was considerably more pronounced than with mutations on the maternal allele. Moreover, birth weights were lower with paternal GNAS mutations affecting exons 2-13 than with exon 1/intron 1 mutations. CONCLUSIONS: These data indicate that a paternally derived GNAS transcript, possibly XLαs, is required for normal fetal growth and development and that this transcript affects placental functions. Thus, similar to other imprinted genes, GNAS controls growth and/or fetal development. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/23884777/Paternal_GNAS_mutations_lead_to_severe_intrauterine_growth_retardation__IUGR__and_provide_evidence_for_a_role_of_XLαs_in_fetal_development_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2013-1667 DB - PRIME DP - Unbound Medicine ER -