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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
Author(s) -
MaupetitMéhouas Stéphanie,
Azzi Salah,
Steunou Virginie,
Sakakini Nathalie,
Silve Caroline,
Reynes Christelle,
Perez de Nanclares Guiomar,
Keren Boris,
Chantot Sandra,
Barlier Anne,
Linglart Agnès,
Netchine Irène
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22352
Subject(s) - gnas complex locus , imprinting (psychology) , genomic imprinting , pseudohypoparathyroidism , locus (genetics) , biology , dna methylation , genetics , methylation , epigenetics , medicine , gene , parathyroid hormone , gene expression , calcium
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 R ussell– S ilver or B eckwith– W iedemann 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 , ICR 1, and ICR 2 on chromosome 11p15, SNRPN , DLK1/GTL2 I G ‐ 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 ( DMR 3), and hypomethylation at PEG1/MEST DMR ( n = 1), (2) hypermethylation at the L3MBTL1 ( DMR 3) ( n = 1) and at the DLK1/GTL2 IG ‐ DMR ( n = 1), and (3) hypomethylation at the L3MBTL1 DMR 3 ( 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.