The purpose of this training grant is to help establish the applicant's independent research career in the field of clinical neurogenetics by investigating the molecular and genetic basis of Joubert syndrome (JS), an autosomal recessive malformation syndrome associated with agenesis of the cerebellar vermis and brainstem malformations. The training environment is the laboratory of Dr. Phillip Chance at the University of Washington, with a track record in mapping and identifying the genes for hereditary neurological disorders. Clinical core features of JS are hypotonia, developmental delay, abnormal respiratory patterns and unusual eye movements. Furthermore, JS exhibits variable additional clinical features (e.g., retinopathy, nephropathy), and is likely to represent a spectrum of disorders with the common feature of cerebellar vermis hypoplasia. Genetic locus heterogeneity is evident. Although loci for JS have been proposed on chromosomes 9q34 and 17pl 1.2, in the majority of JS pedigrees, the locus is unknown and no specific gene has yet been found to be causal for JS. Genes crucial to cerebellar and brainstem development are functional JS candidates, particularly genes specifying the vermian domain and granule cell lineage during cerebellar development. To map an additional gene (or genes) for JS and to determine the molecular basis of this and related disorders, I propose to: 1) Ascertain and collect medical records and blood samples for DNA isolation form multiple families with JS, particularly consanguineous and multiplex pedigrees, 2) develop a prioritized list of candidate genes for JS utilizing genetic methods that include focused haplotype analysis of these genes in consanguineous and multiplex families as well as functional examination of candidate gene expression in human fetal brain tissue, and 3) screen the best candidate genes for mutations in individuals with JS. The fourth and final goal will be to carry out a genome-wide linkage scan to identify loci for JS utilizing a combination of methods employing homozygosity mapping and/or high-resolution linkage analysis in multiplex pedigrees. This project will allow the applicant to complement her experience in clinical genetics and developmental molecular biology with the clinical research skills to define the molecular basis of this important group of cerebellar malformation syndromes.
