title: 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.
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.
authors: Inserm U986, Hôpital Bicêtre-Paris-Sud, Le Kremlin-Bicêtre, France.
authors: Stéphanie
authors: S
authors: Maupetit-Méhouas
authors: Salah
authors: S
authors: Azzi
authors: Virginie
authors: V
authors: Steunou
authors: Nathalie
authors: N
authors: Sakakini
authors: Caroline
authors: C
authors: Silve
authors: Christelle
authors: C
authors: Reynes
authors: Guiomar
authors: G
authors: Perez de Nanclares
authors: Boris
authors: B
authors: Keren
authors: Sandra
authors: S
authors: Chantot
authors: Anne
authors: A
authors: Barlier
authors: Agnès
authors: A
authors: Linglart
authors: Irène
authors: I
authors: Netchine
mesh_terms: D002864:Chromogranins; D015331:Cohort Studies; D019175:DNA Methylation; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018392:Genomic Imprinting; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011547:Pseudohypoparathyroidism / Q000235:genetics* / Q000378:metabolism
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: GNAS; genomic imprinting; growth disorders; uniparental disomy