ESPE Abstracts (2014) 82 FC10.3

Genetic and Epigenetic Defects at the GNAS Locus Lead to Opposite Patterns of Fetal and Postnatal Growth

Virginie Grybeka, Stéphanie Maupetit-Méhouasb, Wolfgang Hoglerc, Harald Jüppnerd, Caroline Silvee & Agnès Linglarte


aINSERM U986-Hôpital Bicêtre, Université Paris Sud, 94276 Le Kremlin Bicêtre, France; bLaboratoire GReD P. Arnaud Team, CNRS 6293-Clermont Université-INSERM U1103, 63001 Clermont-Ferrand, France; cDepartment of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK; dEndocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA; eCentre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphore, Service d’Endocrinologie et Diabétologie de l’Enfant, Université Paris Sud, Hôpital Bicêtre, APHP, 94270 Le Kremlin Bicêtre, France


Background: Pseudohypoparathyroidism (PHP) is characterized by proximal tubular resistance to PTH and, in some disease variants, by Albright osteodystrophy. PHP is caused either by mutations in those regions of GNAS encoding Gsα (PHP1A and PseudoPHP) or by GNAS methylation defects (autosomal dominant (AD) and sporadic (spor) PHP1B). Phenotypic differences in fetal growth, post-natal growth and metabolism are observed in the different PHP types.

Objective and Hypotheses: Our study aimed at understanding the contribution of the different GNAS transcripts to the growth pattern.

Method: We recorded height and weight (birth-18y) of patients with PHP and GNAS mutations or epimutations. GNAS methylation and transcript expressions were measured through pyrosequencing and qRT-PCR from blood and fibroblasts of patients, respectively.

Results: Fetal growth (median(min;max)) was severely and moderately impaired in patients with PseudoPHP and PHP1A. In contrast, it was normal or enhanced in patients with AD-PHP1B and sporPHP1B, and these displayed postnatal overgrowth. Birth length correlated with the methylation at the four differentially methylated GNAS regions, whereas weight correlated with A/B and XLαs promoter methylation. In addition, we showed that methylation of the A/B promoter controls the quantitative expression of A/B transcripts in patients’ fibroblasts and lymphocytes.

Table 1.
PseudoPHP (n=4)PHP1A (n=38)AD-PHP1B (n=9)sporPHP1B (n=22)
Birth length (SDS)−2.89 (−3.04; −1.52)−0.94 (−2.09; 1.01)0.00 (−1.16; 0.85)0.24 (−1.09; 3.26)
Height at 1y (SDS)−0.79 (−1.79; 1.13)−0.64 (−3.04; 1.54)1.36 (0.96; 2.58)2.16 (0.56; 3.83)
BMI at 1y (SDS)−0.76 (−2.19; 0.39)2.62 (−3.25; 5.12)1.5 (0.22; 2.75)1.74 (−1.74; 5.02)
Height at 18y (SDS)−1.64 (−3.25; −0.04)−3.25 (−4.23; −2.18)0.57 (−0.25; 1.39)0.17 (−1.67; 3.83)

Conclusion: Our data suggest that the relative expression of the GNAS transcripts is critical for fetal and postnatal growth.

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