International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Oral Presentation

Tuesday 19 November

09:15 - 09:30 HRS


DR Beier
Harvard Medical School/Brigham and Women's Hosp

Co-Authors: 1) Ackerman KG, 1) Herron BJ, 1) Rao C, 1) Huang H, 2) Babiuk RP,  3) Epstein JA,  2) Greer J
Institutions: 1) Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, 2) Division of Neuroscience, University of Alberta,  3) Cardiovascular Division, University of Pennsylvania Medical School

The power of ENU mutagenesis is the ability to identify in an unbiased fashion the molecular basis of any phenotype amenable to a genetic screen. This is distinct from a genotype-driven analysis, in which the analysis is constrained (to an extent) by the observers' presumption of function. Furthermore, phenotype-driven analysis allows the detection of genes whose hypomorphic function can have deleterious consequences. The biological role of these genes may not be readily appreciated by examination of the null mutant. We are screening ENU-mutagenized mice to identify recessive mutations resulting in developmental abnormalities that are models of human congenital defects.  We identified a mutation that causes pulmonary hypoplasia and abnormal diaphragmatic development. The mutation was mapped to a 1 cM interval, and the identification of flanking markers facilitated the examination of homozygous mice at earlier developmental timepoints.  This revealed that most homozygotes die in mid-gestation with cardiac defects identical to those reported for a targetted mutation of Friend of Gata 2 (Fog2), which is in the recombinant interval. Sequencing revealed a point mutation in a splice donor that results in an intron insertion into the Fog2 transcript, resulting in a truncated protein product. The causal role of the mutation was proven by demonstrating that it fails to complement a Fog2-null mutation.The importance of Fog2 for normal cardiac development has been  shown, but its role in diaphragm and lung development was not previously recognized. Our result demonstrates the utility of a phenotype-driven strategy for understanding the genetic contributions to mammalian development.

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