These authors contributed equally to this work.
Simultaneous Hyper- and Hypomethylation at Imprinted Loci in a Subset of Patients with GNAS Epimutations Underlies a Complex and Different Mechanism of Multilocus Methylation Defect in Pseudohypoparathyroidism Type 1b
Article first published online: 28 MAY 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 8, pages 1172–1180, August 2013
How to Cite
Maupetit-Méhouas, S., Azzi, S., Steunou, V., Sakakini, N., Silve, C., Reynes, C., Perez de Nanclares, G., Keren, B., Chantot, S., Barlier, A., Linglart, A. and Netchine, I. (2013), Simultaneous Hyper- and Hypomethylation at Imprinted Loci in a Subset of Patients with GNAS Epimutations Underlies a Complex and Different Mechanism of Multilocus Methylation Defect in Pseudohypoparathyroidism Type 1b. Hum. Mutat., 34: 1172–1180. doi: 10.1002/humu.22352
Contract grant sponsors: INSERM funding; Paris11 University and Fundacion Eugenio Rodriguez Pascual; Instituto de Salud Carlos III (PI10/0148); la Société Française d'Endocrinologie (SFE); INSERM-ANR EPIFEGRO 2010; I3SNS Program of the Spanish Ministry of Health (CP03/0064; SIVI 1395/09).
Communicated by Ian N. M. Day
- Issue published online: 15 JUL 2013
- Article first published online: 28 MAY 2013
- Accepted manuscript online: 6 MAY 2013 09:18AM EST
- Manuscript Accepted: 29 APR 2013
- Manuscript Received: 24 JAN 2013
- INSERM funding
- Paris11 University and Fundacion Eugenio Rodriguez Pascual
- Instituto de Salud Carlos III. Grant Number: PI10/0148
- la Société Française d'Endocrinologie (SFE)
- INSERM-ANR EPIFEGRO 2010
- I3SNS Program of the Spanish Ministry of Health. Grant Number: CP03/0064; SIVI 1395/09
- genomic imprinting;
- growth disorders;
- uniparental disomy
Most patients with pseudohypoparathyroidism type 1b (PHP-1b) display a loss of imprinting (LOI) encompassing the GNAS locus resulting in PTH resistance. In other imprinting disorders, such as Russell–Silver or Beckwith–Wiedemann syndrome, we and others have shown that the LOI is not restricted to one imprinted locus but may affect other imprinted loci for some patients. Therefore, we hypothesized that patients with PHP-1b might present multilocus imprinting defects. We investigated, in 63 patients with PHP-1b, the methylation pattern of eight imprinted loci: GNAS, ZAC1, PEG1/MEST, ICR1, and ICR2 on chromosome 11p15, SNRPN, DLK1/GTL2 IG-DMR, and L3MBTL1. We found multilocus imprinting defects in four PHP-1b patients carrying broad LOI at the GNAS locus (1) simultaneous hypermethylation at L3MBTL1 differentially methylated region 3 (DMR3), and hypomethylation at PEG1/MEST DMR (n = 1), (2) hypermethylation at the L3MBTL1 (DMR3) (n = 1) and at the DLK1/GTL2 IG-DMR (n = 1), and (3) hypomethylation at the L3MBTL1 DMR3 (n = 1). We suggest that mechanisms underlying multilocus imprinting defects in PHP-1b differ from those of other imprinting disorders having only multilocus loss of methylation. Furthermore, our results favor the hypothesis of “epidominance”, that is, the phenotype is controlled by the most severely affected imprinted locus.