Note: This Abstract has not changed except to reduce the number of mutants characterized in Aim 2 from three plus Lse to two plus Lse, reflecting a reduction in time from four to two years of support as requested for funding via the ARRA. The objectives of this competing renewal are to identify and characterize craniofacial (CF) disorders in mice that are reliable genetic and physiological models for human craniofacial dysmorphologies and to share these models with the scientific public. Discovery of the genetic cause of CF disease in human populations is difficult due to extreme heterogeneity in humans and to the diversity of environmental and nutritional variables, all of which have a role in resulting CF diseases. Consequently, animal models with defined genetic backgrounds maintained in controlled environments are important for CF gene discovery. The proposed research has two initiatives: a) new model discovery and b) phenotypic and molecular development of selected new mutant models.
Aim 1. To discover and characterize new mouse craniofacial mutants to provide the scientific community with genetic and phenotypic models for human CF diseases. This will be accomplished by: a) Taking advantage of the large breeding colonies at TJL and the Phenotypic Deviant Search Program as a source of spontaneous mutations that result in abnormal CF phenotypes;b) Genetically mapping and phenotypically characterizing heritable, highly penetrant new mutants with CF dysmorphologies;c) Advertising the availability of new models using the TJL Craniofacial website that we maintain, TJL's JAXMice website, the """"""""MGI-LIST Digest,"""""""" (an email list that goes out daily to the mouse community daily), flyers at conferences and workshops, presentations at scientific meetings, and peer-reviewed publications;d) Distributing live mice and derivative products from the new mutant strains to external scientists using the established TJL distribution system;e) Providing the opportunity for visiting scientists to screen mutants at TJL.
Aim 2. To identify the causative genes and characterize the phenotypes for two mutants with CF phenotypes, and to continue to pursue gene discovery for Lse (Low set ear). These mutants were chosen for their strong, fully penetrant clinical phenotypes and for their potential to be models for human CF disorders including abnormal skull and eye development, and facial clefting. They are: a) Nm3768, a semi-dominant mutation displaying preaxial polydactlyly, a short nose, dorsal alopecia, abnormal frontal bone development, and eyes open at birth;b) Nm3437, a semi-dominant mutation exhibiting a short nose, a belly spot, partial or complete anophthalmia, facial clefting, holoproencephaly, and severely underdeveloped mandible and facial structures;and c) Lse, a semi-dominant mutation causing low set ears, skull and eye abnormalities.
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