Ornithine Aminotransferase Deficiency in Gyrate Atrophy: Gyrate atrophy (GA) is a blinding, autosomal recessive degenerative disease of the retina and choroid of the eye characterized by a generalized deficiency in the mitochondrial enzyme, ornithine aminotransferase(OAT). Our molecular genetic investigation of this disease has resulted in the cloning and characterization of a cDNA for the human OAT, mapping of the OAT gene sequences to chromosomes 10 and X, identification of the OAT gene family and characterization of the members of the family including the functional OAT gene, construction of expression clones of OAT and expression of OAT in heterologous tissues, and analysis of the OAT gene and its expression in GA patients which has revealed a case with a partial heterozygous deletion of the OAT gene and complete absence of the OAT mRNA. By examining the family members of this GA patient we were able to demonstrate the stable autosomal recessive inheritance of the OAT gene and expression defect in the family in addition to demonstrating the co-dominant mode of action of the OAT gene. Analysis of a GA patient who shows a marked decrease in the level of cellular OAT protein revealed that he is expressing only one of the two alleles of the OAT gene and that the expressed OAT contains a single point mutation resulting in an amino acid change. This amino acid change appears to modify an alpha-helical region of the OAT protein, and assay of the mutant OAT protein for mitochondrial transport/processing seems to indicate that the mutant protein fails to become processed. Hereditary Retinoblastoma and X-linked Ocular Diseases: Work on hereditary retinoblastoma is continuing with isolation of malignant revertants of nonmalignant hybrids between Y79 retinoblastoma and NIH3T3 cells and expression cloning of genes that may alter the phenotype of retinoblastoma. A linkage of the OAT-related X chromosome genes to Norrie Disease and X-linked retinitis pigmentosa has been established using restriction fragment length polymorphisms detected by the OAT probe.
