The broad long-term objective of this research is to find and describe the genes responsible for 2 highly incapacitating hereditary disorders, namely, Diastrophic Dysplasia (DD) and progressive Myoclonus Epilepsy (PME). Nothing is presently known about the pathogenesis of these disorders. When these genes have been described the pathogenesis will become clarified and the way paved for treatment and prevention. It is particularly appropriate for these disorders to be studied in Finland, because they are rare elsewhere but common in Finland. Approximately 150 patients with DD (100 living) and 160 with PME (110 living) have been diagnosed in finland. The distribution of the genes is uneven considerable enrichment in small sub-isolates. This feature makes it possible to use homozygosity mapping in addition to conventional linkage. The first specific aim of this project is to generally map the genes causing DD and PME, with no available data about the nature of the genes of their products, the first will be to search for linkage with random RFLPs. Over 1500 RFLPs that span over 95% of the human genome are available; over 300 polymorphic probes are already in use in the laboratory of the PI. by choosing probes located less than 20 cM apart and distributed as evenly as possible along the chromes, region after region of the human genome will be excluded until positive linkage is found. Blood samples have already been collected and permanent lymphoblastoid cell lines established from 32 DD patients and 75 of their family members representing 14 pedigrees. These samples are sufficient to exclude or establish linkage. For PME the corresponding figures are 20 patients, 30 family members, representing 12 pedigrees. The collection of further samples for PME is underway and will be completed in 1989. Homozygosity mapping will be done using patient DNA from unrelated affected individuals. The second specific aim is to find markers as close as possible to the genes. This will be done by saturating the region with probes. Once closely linked, preferably flanking, markers have been identified, a method based on segregation analysis for carrier detection, and presymptomatic and prenatal diagnosis will be devised. The results of this research should increase the understanding of the biology of DD and PME and provide methods to diagnose and prevent these disorders.
| Hastbacka, J; Kerrebrock, A; Mokkala, K et al. (1999) Identification of the Finnish founder mutation for diastrophic dysplasia (DTD). Eur J Hum Genet 7:664-70 |
| de la Chapelle, A; Wright, F A (1998) Linkage disequilibrium mapping in isolated populations: the example of Finland revisited. Proc Natl Acad Sci U S A 95:12416-23 |
| Hastbacka, J; de la Chapelle, A; Mahtani, M M et al. (1994) The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell 78:1073-87 |
