ESPE Abstracts (2016) 86 RFC10.1

Paternal Loss-of-Function Mutations of GNAS and Growth Retardation in a Mice Model: A Specific Placental Transcriptomic Signature?

Lea Chantal Trana, Celine Ballandonea, Daniel Vaimanb, Sandrine Barbauxb, Nicolas Richarda & Marie-Laure Kottlera

aCMR Phosphorus and Calcium, Department of Genetics, Caen University Hospital, Caen, Normandy, France; bInstitute Cochin (U1016 Inserm/UMR8104 CNRS/UMR-S8104), Paris, Ile de France, France

Background: GNAS gene is a complex imprinted locus, resulting in the expression of at least four transcripts (XL, NESP55, A/B and Gsα) characterized by their specific exon 1 and common exons 2-13. While Gαs is biallelically expressed in most tissues, XL is only expressed from the paternal allele. Maternally inherited, loss-of-function mutations affecting those GNAS exons that encode Gsα cause pseudohypoparathyroidism (PHP) type Ia, a disorder characterized by multiple hormonal resistance. A severe intrauterine growth retardation (IUGR) associated with placental hypotrophy is observed in patients presenting pseudopseudohypoparathyroidism (PPHP) due to paternal GNAS mutations.

Objective and hypotheses: Given the role of placenta in the fetal growth, we suspected an alteration at transcriptional level, due to Gnas loss-of-function mutations. We used different mice models to compare placental transcriptome between wild-type (WT) and heterozygote (KO).

Method: WT female mice were crossed with male mice harboring heterozygote mutation in exon 1 of XL, of E1 or E2 (exon shared between Gsα and XLαs). Placentas were obtained at E18 for each litters and the fetus genotyped. After extraction, placental RNA were hybridized on a microarray (GeneChip Mouse Transcriptome Assay 1.0.), and data were analysed by bioinformatics (GSEA, Webgestalt, String db, Venny Venn).

Results: XL expression is dramatically decreased in XLm+/p− mice (relative quantification vs WT: 0.20, P=<0.0001). We evidenced significant alterations in several genes involved in phenotypes and pathways, such as “Prenatal growth retardation” (P=3.0 ×10−22) and “Decreased placenta weight” (P=2.4×10−10). Transcripts such as Meg3, Mest, Igf2, already described in a IUGR human model (Kappil et al., 2015), were also affected.

Conclusion: Subtle variations of gene networks involving XL would be implicated in the pathogenesis of placental hypotrophy and IUGR associated to GNAS paternal mutation. XL shows a preferential placental expression from the paternal allele.

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