Microphthalmia with Linear Skin Defects (MLS) is an X-linked dominant developmental disorder characterized by linear skin defects on head and neck, microphthalmia, retinal lesions, central nervous system malformations including agenesis of the corpus callosum, seizures, mental retardation and cardiac defects. All MLS patients have a deletion of chromosome Xpter-Xp22, and our laboratory identified two candidate genes in the 450Kb critical interval on Xp22.3. MLS shares phenotypic features with three X-linked non-deletion syndromes: Aicardi syndrome, Goltz syndrome and histiocytic cardiomyopathy and we propose that all four disorders are caused by disruption of the same gene(s). One identified gene encodes for a human holocytochrome c-type synthetase (HCCS) which functions in the mitochondrial respiratory chain and is a good candidate for MLS. Here we propose a five year career development research project to perform mutation analysis of the HCCS gene in the non-deletion disorders and to create an animal model for MLS by generating mice lacking the HCCS gene, and mice with targeted deletions of portions of the MLS region, using homologous recombination in embryonic stem cells. The applicant has developed a strong interest in the molecular biology of normal and abnormal human development and of congenital malformations, during her training in prenatal diagnosis and human genetics and wants to develop a research career in this area. Dr. Zoghbi's laboratory in the Department of Molecular and Human Genetics at Baylor College of Medicine is committed to research on MLS syndrome and provides an excellent environment to develop the candidate's investigative skills. This research will provide insight into the relative contribution of HCCS and other genes, isolated from the MLS region, to the phenotypic features of MLS, Aicardi syndrome, Goltz syndrome and histiocytic CMP. The phenotypic analysis of the various mutant mice will provide insight into the development of the organ systems affected in MLS and provide information on the pathogenesis of related (neuro)developmental disorders.
