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

• Published in: Human mutation Vol. 34; no. 8; pp. 1172 - 1180
• Main Authors: Maupetit-Méhouas, 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
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.08.2013; Hindawi Limited; Wiley
• Subjects: Biochemistry; Biochemistry, Molecular Biology; Chromogranins; Cohort Studies; DNA Methylation; Genomic Imprinting; GNAS; growth disorders; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Protein alpha Subunits, Gs - chemistry; GTP-Binding Protein alpha Subunits, Gs - genetics; GTP-Binding Protein alpha Subunits, Gs - metabolism; Humans; Life Sciences; Polymorphism, Single Nucleotide; Pseudohypoparathyroidism; Pseudohypoparathyroidism - genetics; Pseudohypoparathyroidism - metabolism; uniparental disomy; GNAS; growth disorders; genomic imprinting; uniparental disomy
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22352

ABSTRACT 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. Among patients with PTH resistance due to broad imprinting defect at the locus, some present with loss of imprinting —including hypo or hypermethylation— at several other imprinted loci. In accordance to other multilocus imprinted disorders, the prevailing phenotype is related to the most severely affected imprinted locus.