International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Bjork BC, Vieira AR, Van Parijs L, Murray JC, Beier DR

1 Div. Genetics, Brigham & Women's Hospital, Boston, MA, United States, 2 Dept. Pediatrics, The University of Iowa, Iowa City, IA, United States, 3 Center for Cancer Research, M.I.T., Cambridge, MA, United States

We observe a large spectrum of recessive phenotypes similar to human congenital disorders, including several craniofacial defects, in a late embryonic ENU mutagenesis screen. Clefting occurs in many known mouse mutants, but those with isolated clefts are ideal models of human non-syndromic cleft lip/palate (NSCL/P) (1/500-1000 live births).  The cleft palate only 1 (cpo1; isolated cleft secondary palate) and curly tail/cleft palate (ctcp; cleft secondary palate and/or a curly tail) mutations are excellent models.

 The cpo1 phenotype is likely hypomorphic due to inefficient splicing of a Zn finger transcription factor on chr 4 (Hs. 1p36).  A specific defect in palatal shelf elevation is evident upon histologic evaluation.  cpo1 gene expression during craniofacial development is consistent with its playing an important role in palatogenesis.  We identified three potential etiologic missense mutations in a screen of human NSCL/P cases from Iowa and the Philippines, and a CPO1 haplotype is in strong linkage disequilibrium with Filipino NSCL only and shows a borderline association with Iowa NSCP only, thereby supporting an important role for the CPO1 gene in the complex etiology of NSCL/P. 

We identified a causative nonsense mutation in a novel protocadherin gene on chr 3 (Hs. 4q28) in ctcp mutants.  ctcp gene expression during development is consistent with its phenotype. Identification of downstream target genes and interacting proteins for these genes is in progress.  We are also utilizing lentiviral-expressed RNAi to rapidly “knock down” these genes in mouse embryos and provide confirmation of the etiology of these ENU-induced mutations. 

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