International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

THURSDAY OCTOBER 21

2.45pm – 3.00pm

DISCOVERY OF A GENE CAUSING HUMAN CONGENITAL DIAPHRAGMATIC DEFECT AND PULMONARY HYPOPLASIA BY CHARACTERIZATION OF AN ENU-INDUCED MOUSE MODEL

Ackerman KG1, Vargas SO2, Beier DR1

1 Brigham and Women's Hospital/Harvard Med Sch, Boston, United States, 2 Children's Hospital/Harvard Med Sch, Boston, United States

We are screening embryonic mice for recessive ENU-induced phenotypes similar to human congenital defects. The spectrum of abnormalities found to date is remarkably varied, and many are similar to human malformation syndromes, including, for example, models of asphyxiating thoracic dystrophy, Robin sequence, cleft palate, polycystic kidney disease, and congenital heart defects.

One mutant phenotype includes pulmonary hypoplasia with lobar agenesis and a diaphragmatic muscularization defect, which is similar to the abnormalities found in the often devastating but poorly understood human disorder congenital diaphragmatic hernia (CDH).  Positional cloning revealed that this line carries a hypomorphic mutation of the transcriptional co-factor Fog2. This result itself validates the utility of phenotype-driven analysis, as a requirement for Fog2 in diaphragm and lung development has not been previously recognized.

A role for this gene in CDH was suggested by the association of the disorder with chromosomal translocations at 8q22.3, where human FOG2 is located. To test this, sequencing was done on 30 autopsy samples, and a heterozygous base change resulting in a premature stop codon was identified in one case.  Analysis of the parents revealed that this was a de novo mutation, which strongly implicates FOG2 as causal for CDH in the affected child. No changes at this site were found in 400 normal controls.  

Our identification of FOG2 as the first causal gene for developmental diaphragmatic defects and congenital pulmonary hypoplasia very clearly demonstrates the utility of ENU mutagenesis as a tool for finding candidate genes for human developmental defects. 

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