Trinucleotide repeats consist of three bases consecutively repeated (e.g., CAG CAG CAG CAG CAG CAG CAG) within a region of genomic DNA. Increase in the number of triplets contained within a repeat is a new form of human genetic mutation, known as an expansion mutation. Seven diseases, each with neuropsychiatric features and unusual patterns of inheritance, are caused by expansion mutations. One of these expansion mutations occurs in a gene identified in the laboratory of Dr. Ross. A number of neuropsychiatric disorders, including schizophrenia, bipolar affective disorder, and autism have clinical and neuropathological features and patterns of inheritance similar to the other diseases caused by expansion mutations. In addition, genes with TNRs are frequently transcription factors, and such genes often play a prominent role in neurodevelopment. Together these factors lead to the two hypotheses guiding the proposed research plan: 1) Genes with trinucleotide repeats may regulate aspects of neurodevelopment, and 2) trinucleotide repeat expansion mutation may cause some forms of neuropsychiatric disorders. To test these hypotheses, three specific aims, each tied to a specific career development goal, have been identified. Formal course work and the assistance of collaborators will provide a conceptual context for the technical skills to be acquired in pursuit of each specific aim.
In specific aim #1, the cDNA fragments of previously unidentified genes which contain CAG or CCG repeats will be cloned. The repeats within the clones will be examined for length polymorphisms and collaborators will map each polymorphic clone to a specific loci and test patient DNA for expansion mutation of the newly identified genes.
In specific aims #2 and #3, mRNA and protein expression of selected genes will be examined, with particular emphasis on expression during neurodevelopment. The overall goal of these studies is to identify and characterize genes that are of neurodevelopmental relevance and in which expansion mutations could lead to neuropsychiatric disease.
