ICEECE2012 Oral Communications Bone (6 abstracts)
Simultaneous gain and loss of methylation at imprinted loci in a subset of patients with pseudohypoparathyroidism type 1b and GNAS epimutations
S. Maupetit-Méhouas 1 , S. Azzi 3 , V. Steunou 3 , C. Reynes 6 , C. Silve 1 , A. Barlier 5 , I. Netchine 3, & A. Linglart 1,
1INSERM, Kremlin-Bicetre, France, 2APHP, Kremlin-Bicetre, France; 3INSERM, Paris, France; 4APHP, Paris, France; 5CNRS, Marseille, France; 6Université Paris Diderot, Paris, France.
The majority of patients affected with pseudohypoparathyroidism type 1b (PHP-1b) display loss of imprinting (LOI) encompassing the GNAS locus responsible for decreased Gsa expression in target tissues and PTH resistance. In other imprinting disorders like Silver-Russell, Wiedemann-Beckwith syndromes or transient neonatal diabetes mellitus due to LOI of the imprinted 11p15 and 6q24 regions respectively, we and others have shown that the LOI may spread over to other imprinted loci in some patients. These findings suggested that multilocus imprinted disorders may result from dysfunction(s) of transacting factors.
Therefore, we hypothesized that similar mechanisms may underlie PHP-1b.
We have investigated, in 63 patients affected with PHP-1b, the methylation pattern of six human imprinted loci –in addition to GNAS- ZAC1, PEG1/MEST, ICR1 and ICR2 at 11p15, SNRPN and DLK1/GTL2 IG-DMR.
We found for the first time multilocus imprinting defects in five patients affected with PHP-1b and broad epigenetic changes at the GNAS locus. We observed both gain of methylation at the maternally PEG1/MEST (n=3) and at the paternally DLK1/GTL2 IG-DMR (n=1) methylated loci and loss of methylation at the PEG1/MEST locus (n=1). We propose that the mechanism causing the multilocus imprinting defects in PHP-1b differs from that of other imprinting disorders harboring exclusively loss of methylation in patients with multilocus defects.
Thereby, the epidominance assumption claiming that phenotypes are ruled by the most severely affected imprinted locus seems confirmed by our study, as we did not find clinical differences between patients affected with PHP-1b with or without multilocus defects.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.
Volume 29
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Endocrine Abstracts
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