The objective of this research is to determine the molecular basis of Alstrom Syndrome, a recessive disease characterized by conditions that are frequently observed in the general population. These include progressive aural and retinal insufficiency in their 2nd to 4th decade of life. We localized the Alstrom gene, ALMS1, to Chr. 2p13 by homozygosity mapping in a large French Acadian kindred and by linkage analysis of sporadic families. Currently, the minimal region containing the ALMS1 is less than 1 cM in size and spans 0.6-0.8 Mb of genomic DNA. The specific aims of this proposal include: 1) Identification of the mutant transcript responsible for Alstrom Syndrome and of the spectrum and frequency of mutations within the ALMS1 gene. We will continue to narrow the Alstrom critical region and complete the assembly and annotation of the sequences contained within it by analyzing all of the available sequences in this region, to identify the ALMS1 gene by direct sequencing of transcripts within the region to detect mutations and correlate them to disease phenotypes. (2) Development of a mouse model in order to study Alstrom disease pathology and progression. More specifically, we will identify the temporal and spatial expression pattern of the Alms1 gene, generate a null mutant of the Alms1 gene and evaluate how faithful the model is to the human disease. We will also test whether the phenotypic variability observed in Alstrom Syndrome may be due to genetic modifiers. At the successful conclusion of this proposal, we will have identified the Alstrom gene and generated an animal model to allow for advanced studies of the etiology and pathology of a mutant Alms1 allele. The characteristics of deafness, blindness and obesity have been described in a number of childhood syndromes, suggesting a basic defect in common developmental pathways. Locating and identifying the gene and the molecular defect causing Alstrom may give us insight into what those pathways are. Study of the gene product, its pattern of expression and how it impacts on other genes will lead to better understanding of how normal biological pathways function. In addition, we believe that the identification of the Alstrom gene may provide access to novel metabolic and regulatory pathways involved in the etiology of common complex disease traits described above and related disorders.