title: Detection of hypomethylation syndrome among patients with epigenetic alterations at the GNAS locus.
abstract: Genomic imprinting is the modification of the genome so that genes from only one (rather than two) of the parental alleles are expressed. The mechanism underlying imprinting is epigenetic, occurring via changes in DNA methylation and histone modifications rather than through alterations in the DNA sequence. To date, nine different imprinting disorders have been clinically and genetically identified and a considerable research effort has been focused on determining the cause of the corresponding methylation defects.
  
  
  
  Our objective was to identify multilocus imprinting defects and characterize any mutations in trans-acting genes in patients with pseudohypoparathyroidism (PHP) caused by epigenetic alterations at GNAS locus.
  
  
  
  We have investigated multilocus imprinting defects in 22 PHP patients with aberrant methylation at the GNAS locus not due to previously described deletions or to paternal uniparental disomy (UPD) of chromosome 20.
  
  
  
  We found that, in contrast to what has been described in growth disorders, multilocus hypomethylation is an uncommon event in PHP patients. We were also unable to identify any genetic alteration causative of the epigenetic defects in the currently known methylation regulatory genes.
  
  
  
  Our work suggests that a trans-acting gene regulating the establishment or maintenance of imprinting at GNAS locus, if it exists, should be specific to PHP cases caused by epigenetic defects at GNAS.
authors.affiliation: Molecular (Epi)Genetics Lab Research Unit, Hospital Txagorritxu, E-01009, Vitoria-Gasteiz, Alava, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Perez-Nanclares
authors.forename: Valeria
authors.initials: V
authors.lastname: Romanelli
authors.forename: Sonia
authors.initials: S
authors.lastname: Mayo
authors.forename: Intza
authors.initials: I
authors.lastname: Garin
authors.forename: Celia
authors.initials: C
authors.lastname: Zazo Seco
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernandez-Rebollo
authors.forename: Francisco
authors.initials: F
authors.lastname: Martínez
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.forename: Guiomar Pérez
authors.initials: GP
authors.lastname: de Nanclares
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D019175:DNA Methylation / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D014644:Genetic Variation; D018392:Genomic Imprinting / Q000502:physiology*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D055815:Young Adult
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs