Journal
HUMAN MUTATION
Volume 34, Issue 8, Pages 1172-1180Publisher
WILEY
DOI: 10.1002/humu.22352
Keywords
genomic imprinting; GNAS; growth disorders; uniparental disomy
Categories
Funding
- INSERM
- Paris11 University
- Fundacion Eugenio Rodriguez Pascual
- Instituto de Salud Carlos III [PI10/0148]
- la Societe Francaise d'Endocrinologie (SFE)
- INSERM-ANR EPIFEGRO
- I3SNS Program of the Spanish Ministry of Health [CP03/0064, SIVI 1395/09]
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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/MESTDMR (n=1), (2) hypermethylation at the L3MBTL1 (DMR3) (n=1) and at the DLK1/GTL2IG-DMR (n=1), and (3) hypomethylation at the L3MBTL1DMR3 (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.
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