International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

MONDAY OCTOBER 18

5.15pm – 5.30pm

MUTATIONS THAT CAUSE HETEROZYGOUS EYE DEFECTS ARE LETHAL WHEN HOMOZYGOUS AND MODEL HUMAN DISEASE

Cross SH1, Hart AW1, Morgan JE1, McKie L1, West K1, Schneider JE2, Bhattacharya S2, Jackson IJ1

1 MRC Human Genetics Unit, Edinburgh, United Kingdom, 2 Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

ENU mutagenesis is a powerful tool for revealing gene function. We have produced a collection of 25 ENU-induced mutants with a variety of eye defects and most of these are homozygous lethal. Three– Rwhs, Icst and Dilp2 (an X-linked male lethal) – map to novel loci. We used high-throughput magnetic resonance imaging (MRI) of embryos to determine the mechanism of lethality in these mutants. This enables us to screen 32 embryos per overnight run, retains 3D information and allows embryos to be examined in any section plane. Using MRI, we found that Rwhs homozygotes have pulmonary hypoplasia and Bochdalek congenital diaphragmatic hernia. This malformation is present in 1:2500 live births, and even with corrective surgery has a mortality of ~30%. Icst homozygotes have a ventricular septal defect and aberrant right-sided aortic arches. Dilp2 males have a common arterial trunk, a condition that accounts for 1% of all congenital heart defects. In addition they have palate defects and the absence of a sternum.

The critical genetic intervals for each of these do not contain any previously described candidate genes but are now sufficiently small to start scanning the genes present for mutations. It is noteworthy that numerous of our mutations that give a dominant eye phenotype affect organogenesis and are lethal when homozygous. Importantly, all three model conditions that are relevant for human disease.

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