title: Loss of methylation at GNAS exon A/B is associated with increased intrauterine growth.
abstract: BACKGROUND
  GNAS is one of few genetic loci that undergo allelic-specific methylation resulting in the parent-specific expression of at least four different transcripts. Due to monoallelic expression, heterozygous GNAS mutations affecting either paternally or maternally derived transcripts cause different forms of pseudohypoparathyroidism (PHP), including autosomal-dominant PHP type Ib (AD-PHP1B) associated with loss of methylation (LOM) at exon A/B alone or sporadic PHP1B (sporPHP1B) associated with broad GNAS methylation changes. Similar to effects other imprinted genes have on early development, we recently observed severe intrauterine growth retardation in newborns, later diagnosed with pseudopseudohypoparathyroidism (PPHP) because of paternal GNAS loss-of-function mutations.
  
  
  OBJECTIVE
  This study aimed to determine whether GNAS methylation abnormalities affect intrauterine growth.
  
  
  METHODS
  Birth parameters were collected of patients who later developed sporPHP1B or AD-PHP1B, and of their healthy siblings. Comparisons were made to newborns affected by PPHP or PHP1A.
  
  
  RESULTS
  As newborns, AD-PHP1B patients were bigger than their healthy siblings and well above the reference average; increased sizes were particularly evident if the mothers were unaffected carriers of STX16 deletions. SporPHP1B newborns were slightly above average for weight and length, but their overgrowth was less pronounced than that of AD-PHP1B newborns from unaffected mothers.
  
  
  CONCLUSIONS
  LOM at GNAS exon A/B due to maternal STX16 deletions and the resulting biallelic A/B expression are associated with enhanced fetal growth. These findings are distinctly different from those of PPHP patients with paternal GNAS exons 2-13 mutations, whose birth parameters are almost 4.5 z-scores below those of AD-PHP1B patients born to healthy mothers.
authors.affiliation: Department of Genetics (A.-C.B., C.C., N.R., M.-L.K.), Centre Hospitalier Universitaire de Caen, Reference Centre for Rare Disorders of Calcium and Phosphorus Metabolism, F-14000 Caen, France; Paediatric Endocrinology and Diabetology (S.M.-M., V.G., A.L.), Reference Centre for Rare Disorders of the Mineral Metabolism, AP-HP Hôpital Bicêtre, le Kremlin-Bicêtre 94270, France; Faculté de Médecine, Université Paris Sud, le Kremlin-Bicêtre 94270, France; and Pediatric Nephrology Unit and Endocrine Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Bréhin
authors.forename: Cindy
authors.initials: C
authors.lastname: Colson
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Maupetit-Méhouas
authors.forename: Virginie
authors.initials: V
authors.lastname: Grybek
authors.forename: Nicolas
authors.initials: N
authors.lastname: Richard
authors.forename: Agnès
authors.initials: A
authors.lastname: Linglart
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Kottler
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
mesh_terms: D001724:Birth Weight / Q000235:genetics; D002864:Chromogranins; D019175:DNA Methylation; D005091:Exons / Q000235:genetics; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D005320:Fetal Macrosomia / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011547:Pseudohypoparathyroidism / Q000235:genetics; D012189:Retrospective Studies; D051438:Syntaxin 16 / Q000235:genetics
chemical_list: D002864:Chromogranins; C496118:STX16 protein, human; D051438:Syntaxin 16; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs