The objectives of the proposed research are to identify and characterize in mice craniofacial disorders that are reliable genetic and physiological models for human craniofacial dysmorphologies and to share these models with the scientific public. The proposed research will include screening for new spontaneous and induced mutations, comprehensive genetic studies, preliminary characterization studies (clinical examination, basic histology, evaluation of bone density and skeletal anomalies, dentition, vision and hearing), and identification of the mutated gene in the best models by candidate gene testing and positional cloning. We will provide these models to the scientific community expeditiously via website notification and will distribute live mice using programs already in place at The Jackson Laboratory. This proposal has three specific aims: 1. To discover and characterize (genetically and phenotypically) new mouse craniofacial mutations to provide the scientific community with model systems for research on facial, dental, eye, ear, and skull development and mouse models of human craniofacial syndromes. 2. To identify the mutated genes in three new mutants already genetically mapped and partially characterized: Dhe, a semi-dominant mutation causing an underdeveloped lower jaw, abnormal tooth development, small ears, and a sparse, rough coat; Lse, a semi-dominant mutation causing low set ears, skull and eye abnormalities, and nee, a recessive mutation causing a blunted face, bulging eyes, and intermediate hearing loss. 3. To execute a sharing plan whereby new models will be made available rapidly to the scientific community through our established web sites and live mice will be distributed via the existing shipping program within The Jackson Laboratory. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015073-02
Application #
6725500
Study Section
Special Emphasis Panel (ZDE1-YL (03))
Program Officer
Chin, Hemin R
Project Start
2003-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$407,500
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Fairfield, Heather; Srivastava, Anuj; Ananda, Guruprasad et al. (2015) Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders. Genome Res 25:948-57
Curtain, Michelle; Heffner, Caleb S; Maddox, Dennis M et al. (2015) A novel allele of Alx4 results in reduced Fgf10 expression and failure of eyelid fusion in mice. Mamm Genome 26:173-80
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Fairfield, Heather; Gilbert, Griffith J; Barter, Mary et al. (2011) Mutation discovery in mice by whole exome sequencing. Genome Biol 12:R86
Pratt, C Herbert; Curtain, Michelle; Donahue, Leah Rae et al. (2011) Mitotic defects lead to pervasive aneuploidy and accompany loss of RB1 activity in mouse LmnaDhe dermal fibroblasts. PLoS One 6:e18065
Odgren, Paul R; Pratt, Craig H; Mackay, Carole A et al. (2010) Disheveled hair and ear (Dhe), a spontaneous mouse Lmna mutation modeling human laminopathies. PLoS One 5:e9959
Mao, Mao; Thedens, Daniel R; Chang, Bo et al. (2009) The podosomal-adaptor protein SH3PXD2B is essential for normal postnatal development. Mamm Genome 20:462-75
Beamer, Wesley G; Shultz, Kathryn L; Ackert-Bicknell, Cheryl L et al. (2007) Genetic dissection of mouse distal chromosome 1 reveals three linked BMD QTLs with sex-dependent regulation of bone phenotypes. J Bone Miner Res 22:1187-96
Xia, Chun-hong; Liu, Haiquan; Chang, Bo et al. (2006) Arginine 54 and Tyrosine 118 residues of {alpha}A-crystallin are crucial for lens formation and transparency. Invest Ophthalmol Vis Sci 47:3004-10

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