International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)

POSTER 177 - Two imprinted phenotypes from one ENU mutation: positional cloning of oedematous-small

J A Skinner
MRC Mammalian Genetics Unit
OX11 0RD

Co-Authors: Cattanach BM, Sanderson M, Armour M, Hobbs L, Morse S, Peters J 
Institutions: MRC Mammalian Genetics Unit

A mutant arising from an ENU-mutagenesis experiment has been shown to display two different phenotypes dependent upon which parental allele carries the mutation. When the mutation is transmitted though the mother the mice show gross oedema prenatally and at birth. When the mutation is transmitted through the father the mice typically appear normal up to birth but show growth retardation over the first few days. The mutation has been named oedematous-small (Oed-Sml).

Linkage analysis has mapped the mutation to distal Chr 2, a region known to contain imprinted genes. The interval containing Oed-Sml lies between D2Mit113 and D2Mit213 and includes the Gnas cluster responsible for a number of oppositely imprinted and alternatively spliced transcripts. Of these, Nesp, Gnasxl, and Gnas exon1A all splice onto exon2 of Gnas. Nesp is maternally expressed whereas Gnasxl, Gnas exon1A and the antisense Nespas are paternally expressed. Gnas itself is largely biallelically expressed but shows maternal expression in specific tissues.

A model for oedematous-small has been proposed whereby the mutation has occurred in two oppositely imprinted transcripts in the Gnas cluster. The first candidates tested were Nesp and Nespas, two oppositely imprinted sense and antisense transcripts. These have now been excluded by RNA analysis and sequencing of Nesp cDNA. Other possible candidates are being investigated by sequencing this region. A point mutation within the coding sequence of Gnas has now been identified. This is a very strong candidate because it affects both maternal and paternal specific transcripts. Investigations are continuing.

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