International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 142 - PHENOTYPIC CHARACTERIZATION AND POSITIONAL CLONING OF CRANIOFACIAL MUTANTS GENERATED FROM A RECESSIVE ENU MUTAGENESIS SCREEN

BC Bjork
Brigham and Women’s Hospital, Harvard Medical School

2) Herron BJ, 3) Justice MJ, 4) McDonald D, 5) Beier DR
1) Brigham and Women’s Hospital, Harvard Medical School, 2) Genomics Institute, 3) Baylor College of Medicine, 4) Wichita State University, 5) Brigham and Women’s Hospital, Harvard Medical School

ENU mutagenesis has proven to be a powerful means by which to generate single nucleotide mutations in mice.  We are screening E18.5 embryos from ENU-treated mice for recessive phenotypes that resemble human congenital disorders.  The screen is performed as an outcross to facilitate the rapid localization of the mutant loci using a strategy of interval haplotype analysis.  Among the large spectrum of phenotypic abnormalities we have identified are a significant number of defects involving craniofacial development, including nonsyndromic and syndromic cleft primary and secondary palate.Orofacial clefting is a major human congenital disorder with a complex etiology and a high incidence (1/500 to 1/2500 live births) depending on a variety of factors.  Many known mouse mutants contain orofacial clefts as part of their phenotype, but the best models for human clefting are those with clefts in the absence of additional phenotypes.  In an analysis of 54 families for recessive mutations, we identified four models of orofacial clefting including cleft palate only 1 (cpo1; cleft secondary palate with no additional phenotypic abnormalities detected), curly tail/cleft palate (ctcp; variable expression of cleft secondary palate, a curly or kinked tail and bent forelimbs) and little chin (cleft secondary palate and a small mandible that resembles the abnormalities observed in the Pierre Robin syndrome).  Most recently, we identified cleft lip/palate 3 (cleft primary and/or secondary palate with no additional phenotypic abnormalities detected).  We report the genetic localization, fine-mapping, developmental characterization and candidate gene screening for these ENU-induced recessive mutations.


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