International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Cross SH
MRC Human Genetics Unit

Co-Authors: 1) Thaung C, 1,2) Morgan J, 1) West K, 1) McKie L, 1) Brunet J F, 3) Brown SDM, 2) Jackson I J
Institutions: 1) MRC Human Genetics Unit, 2) MRC Mammalian Genetics Unit 3) Ecole Normale Supérieure

One way of revealing gene function is to introduce point mutations into genes using the powerful mutagen ENU and then examine mice carrying the mutations for abnormal phenotypes. We have produced a collection of 25 ENU-induced mutants with a variety of eye defects. For 17 of these the gene affected and the molecular defect, in each case a single point mutation, has been identified. All but one of the characterised mutations are in human eye disease genes and we have mouse models of recessive retinal degeneration, Waardenburg syndrome type IIA, renal-coloboma syndrome, aniridia and cataract. Included amongst these are mutations that produce loss-of-function, dominant negative and hypomorphic alleles. One mutant, Dilp1, has dilated pupils and is caused by a sequence change that introduces a stop codon in the first exon of Phox2b. It does not complement a Phox2b knock-out and when homozygous Dilp1 causes embryonic lethality. Phox2b is a homeobox gene important for the development for the autonomic nervous system. It has not previously been implicated in eye disease, although polyalanine and frameshift mutations in PHOX2B have been found in patients with congenital central hypoventilation syndrome. Three of the unassigned mutations cause a similar dominant dilated pupils phenotype and one is an X-linked male lethal, the homozygous phenotype of the others is still being assessed. None map to genomic regions known to contain human eye disease genes. One expectation is that these will also be mutations of genes important for development of the autonomic nervous system.

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