title: A new deletion ablating NESP55 causes loss of maternal imprint of A/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib.
abstract: BACKGROUND
  Patients with pseudohypoparathyroidism type Ib (PHP-1b) develop resistance toward PTH, leading to hypocalcemia and hyperphosphatemia. PHP-1b is an imprinted human disorder associated with methylation changes at one or several differentially methylated regions at the GNAS locus. This complex locus gives rise to several different transcripts with different patterns of imprinted expression depending on promoter methylation. They can be either coding [Gαs, XLαs, and neuroendocrine secretory protein-55 (NESP55)] or nontranslated (A/B and AS). The paternal AS transcript lies antisense to nesp55.
  
  
  OBJECTIVE
  Define the genetic defect in a new family with three patients presenting autosomal dominant PHP-1b.
  
  
  METHODS
  We used methylation analysis, comparative genomic hybridization, and genotyping to characterize the defect. AS expression was studied in two patients and their unaffected mothers.
  
  
  RESULTS
  A novel deletion of 18,988 bp that removes NESP55 and a large part of its counterpart GNAS AS intron 4 was discovered. On maternal transmission, this deletion causes loss of A/B methylation without affecting XL/AS imprint. On paternal transmission, there are no methylation anomalies. The deletion creates a cryptic exon contained within AS intron 4, which is expressed from the mutated allele, be it paternal or maternal.
  
  
  CONCLUSIONS
  This new deletion suggests that NESP55 is an additional imprinting control region that directs A/B methylation in humans. We bring arguments in support of the theory of reciprocal inhibition between the expression of NESP and AS. However, determining whether loss of methylation at the A/B differentially methylated region is a consequence of the loss of NESP expression or of the expression of AS requires additional investigations.
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Caen, Department of Genetics, Caen F-14033, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Richard
authors.forename: Genevieve
authors.initials: G
authors.lastname: Abeguilé
authors.forename: Nadia
authors.initials: N
authors.lastname: Coudray
authors.forename: Hervé
authors.initials: H
authors.lastname: Mittre
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gruchy
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.forename: Pascal
authors.initials: P
authors.lastname: Cathebras
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Kottler
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002864:Chromogranins; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011547:Pseudohypoparathyroidism / Q000235:genetics*
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs