title: The imprinted oedematous-small mutation on mouse chromosome 2 identifies new roles for Gnas and Gnasxl in development.
abstract: The Gnas locus is highly complex and encodes several oppositely imprinted and alternatively spliced transcripts. Gnas itself encodes Gsalpha, which is involved in endocrine function and bone development, but the roles for the other transcripts have not been established. Here we describe a mouse mutation that provides further biological functions for the Gnas locus. The mutation Oed-Sml, induced by ethylnitrosourea (ENU), has been mapped to the distal chromosome 2 imprinting region that includes Gnas. The mutation displays two distinct phenotypes dependent on parental origin. When the mutation is maternally transmitted, a microcardia with gross edema (Oed) results. By contrast, when the mutation is paternally transmitted, a growth retardation (Sml) is seen that becomes evident within 5 days of birth. Here we show Oed-Sml to be a point mutation in Gnas exon 6, resulting in a valine to glutamate substitution at residue 159 (V159E). Both maternal- and paternal-specific transcripts derive from this missense mutation. The maternally expressed mutant Gnas transcript is the candidate for Oed and the paternally expressed mutant Gnasxl transcript is the candidate for Sml. We propose a new role for Gnas in heart growth and a role for Gnasxl in postnatal growth. These findings potentially have implications for human Albright hereditary osteodystrophy, a condition caused by mutations in GNAS.
authors.affiliation: Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire OX11 ORD, UK.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Skinner
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cattanach
authors.forename: Jo
authors.initials: J
authors.lastname: Peters
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002864:Chromogranins; D019205:GTP-Binding Protein alpha Subunits, Gs; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D006128:Growth / Q000235:genetics*; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: D002864:Chromogranins; D009419:Nerve Tissue Proteins; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins