Genetic and anatomic basis of the fibrosis syndromes

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DESCRIPTION (provided by applicant): The congenital fibrosis syndromes are oculomotility disorders characterized by restrictive ophthalmoplegia with or without ptosis, and each disorder varies in the fixed position of the globes and in the specifically affected cranial nerve(s) and extraocular muscles (EOMs). The neuropathologic bases of two fibrosis syndromes have been described; Duane syndrome results from absence of the abducens nerve and nucleus, while CFEOM1 results from an absence of the superior division of the oculomotor nerve and corresponding oculomotor subnuclei. The laboratory's long-term goals are to uncover the molecular basis of the fibrosis syndromes and to study the development of the oculomotor lower motor neuron system. Toward these goals, we have genetically defined four congenital fibrosis loci and one congenital ptosis locus, and are in the process of positionally cloning these genes. In this grant, we seek funding to address the following specific aims: (1) Identify families with the congenital fibrosis syndromes for our clinical and genetic studies and analyze their DNA for linkage to the known CFEOM loci. (2) Define the anatomic and functional basis of CFEOM by high-resolution orbital MRI studies in affected members of genetically defined families. (3) Clone the CFEOM1 disease gene (which is mutated in the most common inherited form of the congenital fibrosis syndromes) and analyze CFEOM1 families for disease-causing mutations. (4) Initiate structural and functional characterization of the CFEOM1 RNA and protein product. Significance: The molecular bases of strabismic disorders remain poorly understood. Though rare, several of the fibrosis syndromes are inherited, and thus provide a unique opportunity to investigate the etiology of this subset of strabismic disorders. Our large collection of CFEOM1 families, coupled with a detailed physical map and access to genomic sequence within the CFEOM1 critical region, places us in a unique position to identify this disease gene. In addition, the correlation of this genetic data with the proposed clinical, anatomic, and functional characterization of genetically defined patients provides a unique and strong foundation for phenotype-genotype correlations and functional studies. By defining the genetic and anatomic bases of CFEOM1, we will develop a tool with which to study its molecular basis and to search for related fibrosis genes, and with which we should gain important new insights into brainstem cranial nerve development. These data will be invaluable to our understanding of the developmental roles of these genes, and should also contribute to improved therapy of the fibrosis syndromes.