title: Exclusion of the GNAS locus in PHP-Ib patients with broad GNAS methylation changes: evidence for an autosomal recessive form of PHP-Ib?
abstract: Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation.
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernández-Rebollo
authors.forename: Guiomar
authors.initials: G
authors.lastname: Pérez de Nanclares
authors.forename: Beatriz
authors.initials: B
authors.lastname: Lecumberri
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
authors.forename: Emma
authors.initials: E
authors.lastname: Anda
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pérez-Nanclares
authors.forename: Denice
authors.initials: D
authors.lastname: Feig
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.forename: Murat
authors.initials: M
authors.lastname: Bastepe
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D001483:Base Sequence; D002864:Chromogranins; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005091:Exons / Q000235:genetics; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002864:Chromogranins; C502448:NLRP7 protein, human; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs