The Imprinted Oedematous-Small Mutation on Mouse Chromosome 2 Identifies New Roles for Gnas and Gnasxl in Development

The Gnas locus is highly complex and encodes several oppositely imprinted and alternatively spliced transcripts. Gnas itself encodes Gsα, 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.