Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development.

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: Nicolas Richard, Arnaud Molin, Nadia Coudray, Pauline Rault-Guillaume, Harald Jüppner, Marie-Laure Kottler
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 98 Issue 9 Pg. E1549-56 (Sep 2013) ISSN: 1945-7197 [Electronic] United States
• PMID: 23884777 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromogranins
• GNAS protein, human
• GTP-Binding Protein alpha Subunits, Gs

Topics

• Adolescent
• Adult
• Alleles
• Bone Diseases, Metabolic (genetics)
• Child
• Child, Preschool
• Chromogranins
• Exons
• Female
• Fetal Development (genetics)
• Fetal Growth Retardation (genetics)
• GTP-Binding Protein alpha Subunits, Gs (genetics)
• Heterozygote
• Humans
• Infant
• Infant, Newborn
• Infant, Small for Gestational Age
• Male
• Mutation
• Ossification, Heterotopic (genetics)
• Pseudopseudohypoparathyroidism (genetics)
• Retrospective Studies
• Skin Diseases, Genetic (genetics)