In the last eight years, Dr. Polymeropoulos's laboratory has been involved in a program aimed at the understanding of the molecular basis of human inherited disorders. Beyond the direct application of molecular genetics tools my program has also included development of genomics tools.

During the formative phases of the modern genetic maps, his lab team developed and mapped numerous genetic markers based on simple sequence repeats either from human genomic DNA or from the untranslated regions of cDNAs. In 1991 with the demonstration tha t human cDNAs could be efficiently sample sequenced, it was apparent that gene hunting efforts would be greatly aided if the genes were mapped on the physical maps of the human genome. His laboratory pioneered the massive mapping of expressed sequence tag s (ESTs), an effort that lead to the development of the IMAGE consortium for the characterization and mapping of human expressed sequences. This effort grew to an international collaboration, and the recent publication in 1996 of the first generation tran script map of the human genome, with 16,000 human transcripts. While they were investing in the development of genomic analysis tools, they also pursued the goal of understanding the molecular basis of human inherited disorders.

As the genetic maps matured they allowed for the rapid mapping of susceptibility genes for human Mendelian disorders. Using family material for a number of disorders they were able to rapidly identify the locations in the genome. The genes localized inclu ded, Wolfram syndrome, Proximal Symphalangism, Pyknodysostosis, Ellis van Creveld, Neimann Pick type C, Cystinosis, Cavernous angiomas, Synpolydactyly, Brachydactyly type C and most recently a gene for Parkinson's disease. However, while the mapping tools are very efficient, positional cloning remains a challenge. In Polymeropoulos's laboratory they have pursued the positional cloning of three genes: Wolfram syndrome, Ellis van Creveld and Parkinson's disease.

Wolfram syndrome, a rare autosomal recessive syndrome with diabetes mellitus and optic atrophy is also characterized by an increased risk for severe psychiatric illness, not only in the homozygote affected but in the heterozygote carriers. They have recen tly shown that carrier status for the Wolfram gene gives a 20 fold increase in risk for development of psychiatric symptoms. The Ellis van Creveld gene maps in a genomic region on 4p16, included in the region harboring the Wolfram gene. Therefore, they ha ve initiated a positional cloning effort aimed at both genes located in a region of approximately 2cM. The Wolfram project is done in collaboration with the laboratory of Dr. Michael Swift and the EVC project with Dr. Claire Francomano.

Genetic tools have proven successful in the analysis of Mendelian disorders; however application of the same tools in the study of complex disorders has proven challenging. Last year they began an effort aimed at the understanding of genetic factors invol ved in the pathogenesis of Parkinson's disease. The effort was initiated using the model of Mendelian traits, in a large family with autosomal dominant Parkinson's disease with a calculated penetrance of 85%. The lab team's hope was that by concentrating in the study of just one kindred with highly penetrant disease they could effectively reduce the complexity of genetic factors. Genetic linkage analysis was restricted to affected only individuals. Scanning of the genome soon resulted to the identificatio n of a susceptibility locus on the long arm of human chromosome 4. A positional cloning effort was soon initiated that resulted in identification of the mutation, an Ala to Thr substitution in alpha synuclein at position 53 (Ala53Thr). The team has shown that a missense mutation in the alpha synuclein gene is responsible for the illness in the initial pedigree and three additional unrelated families.