title: Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development.
abstract: BACKGROUND
  Heterozygous GNAS inactivating mutations cause pseudohypoparathyroidism type Ia (PHP-Ia) when maternally inherited and pseudopseudohypoparathyroidism (PPHP)/progressive osseous heteroplasia (POH) when paternally inherited. Recent studies have suggested that mutations on the paternal, but not the maternal, GNAS allele could be associated with intrauterine growth retardation (IUGR) and thus small size for gestational age.
  
  
  OBJECTIVE
  The aim of the study was to confirm and expand these findings in a large number of patients presenting with either PHP-Ia or PPHP/POH.
  
  
  METHODS
  We collected birth parameters (ie, gestational age, weight, length, and head circumference) of patients with either PHP-Ia (n = 29) or PPHP/POH (n = 26) with verified GNAS mutations. The parental allele carrying the mutation was assessed by investigating the parents or, when a de novo mutation was identified, through informative intragenic polymorphisms.
  
  
  RESULTS
  Heterozygous GNAS mutations on either parental allele were associated with IUGR. However, when these mutations are located on the paternal GNAS allele, IUGR was considerably more pronounced than with mutations on the maternal allele. Moreover, birth weights were lower with paternal GNAS mutations affecting exons 2-13 than with exon 1/intron 1 mutations.
  
  
  CONCLUSIONS
  These data indicate that a paternally derived GNAS transcript, possibly XLαs, is required for normal fetal growth and development and that this transcript affects placental functions. Thus, similar to other imprinted genes, GNAS controls growth and/or fetal development.
authors.affiliation: Centre Hospitalier Universitaire de Caen, Department of Genetics, Reference Centre for Rare Disorders of Calcium and Phosphorus Metabolism, F-14000 Caen, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Richard
authors.forename: Arnaud
authors.initials: A
authors.lastname: Molin
authors.forename: Nadia
authors.initials: N
authors.lastname: Coudray
authors.forename: Pauline
authors.initials: P
authors.lastname: Rault-Guillaume
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Kottler
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001851:Bone Diseases, Metabolic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D005091:Exons; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D005317:Fetal Growth Retardation / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D008297:Male; D009154:Mutation; D009999:Ossification, Heterotopic / Q000235:genetics; D011556:Pseudopseudohypoparathyroidism / Q000235:genetics; D012189:Retrospective Studies; D012873:Skin Diseases, Genetic / Q000235:genetics
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs