Identification of a gene involved in multiple sclerosis in a genetically isolated population
08 / 2005 - 08 / 2008
Stichting MS Research
Multiple Sclerosis (MS) is a complex genetic disorder. HLA region plays a crucial role in the susceptibility to MS, but it is clear that other genes must be involved. As part of our pilot study funded by MS Research, we have identified 48 patients in our Genetic Research in Isolated Populations (GRIP) program. With the financial support of MS Research, we have performed a genome screen in 38 MS patients and 55 relatives. The strongest evidence for a MS-locus was found for chromosome 4 at markers D4S405 and D4S392 (overall LOD-score 2.1) using homozygosity mapping. A total of 7 patients were found to be homozygous for the same allele at D4S405, suggesting there may be a recessive mutation involved in the pathogenesis of the disease in these patients. Furthermore there is some evidence for a second peak at chromosome 5 with a maximum LOD score of 1.6 between markers D5S641 and D5S644. Our findings are supported by several studies on the genetics of MS and therefore we ask for further research. The aim of the present study is to identify the gene located on chromosome 4 that is implicated in MS. In the first step of the proposal, we aim to narrow down the region using 40 Single Nucleotide Polymorphisms (SNPs) and identify new families in which the relatives share the same haplotype at chromosome 4. We will not only study patients identified in GRIP but we will also include 160 patients with a familial form of MS and 440 unaffected relatives who are derived from the general Dutch population. This will allow us (1) to confirm our findings in patients derived from GRIP in an independent series of patients and (2) to characterize the chromosome 4 region further. In the second step we will fully saturate the region in those patients who share the chromosome 4 haplotype and will sequence (candidate) genes in the region for mutations explaining the disease.