Genetics of the carbohydrate-deficient glycoprotein syndrome type Ia

Sammanfattning: In recent years, a revolution in the development of new techniques have made it possible to perform genetic studies of inherited disorders without prior knowledge about the gene product or the function of the gene. The techniques include linkage studies, allelic association studies, physical mapping and the sequencing of candidate genes for finding disease causing mutations. This thesis describes one such case; genetic linkage studies led to the characterization of a chromosomal location and together with studies from other laboratories, to the identification and detailed characterization of the disease gene involved. About 20 years ago, the carbohydrate-deficient glycoprotein (CDG) syndrome was first discovered in a monozygous twin pair. Within a few years several children were diagnosed to have the same syndrome based on clinical and biochemical analysis. The CDG syndrome type Ia has an early neonatal presentation and all children develop cerebellar atrophy, mental retardation and a psychomotor delay. The biochemical characteristics of the syndrome are complex defects in the carbohydrate residues of many serum glycoproteins. In Sweden approximately one child in 70,000 is born with the CDG syndrome and 30% of these children die before the age of five.The overall aim of this study was to find the genetic alteration which causes the CDG syndrome type Ia and to understand the biochemical changes that characterize the syndrome. The study started in 1993 with 25 CDG type Ia patients. In the first paper (published in 1994) we could, for the first time, map the gene to chromosome 16p13 (CDG1 gene region). Significant linkage disequilibrium could also be demonstrated for one of the polymorphic markers located in the CDG1 gene region. The next paper (1997) presented the fine mapping of this region. We could in this paper delimit the region from 13cM to less than 1cM and less than 1Mb based on the specific haplotype found mainly in Scandinavian families. This was a region small enough for physical mapping. In the third paper (1998) we could present data on fine mapping of the PMM2 gene and on a mutation in the PMM2 gene that correlated to the specific Scandinavian haplotype. An evaluation was also done of 15 prenatal diagnostic cases. The last paper (2000) presents the complete PMM2 gene mutation spectrum of the CDG type Ia patients in our study. Most of the mutations were found in exon 5 (61%) and exon 8. A conclusion drawn from this is that exon 5 should be screened first in prenatal diagnostic cases.Specific genetic alterations can open up new possibilities for better diagnostic tools of both carrier and prenatal situations and hence help such families. Furthermore this study can result in a better understanding of the glycosylation pathway and in the future be of help for understanding the genetic explanation of other CDG variants. Finally the information obtained in this study can comprise the basis for the development of adequate therapy.