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Combined factors V and VIII deficiency--the solution
D Ginsburg1, W C Nichols, A Zivelin
1Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
Insights
Combined deficiency of coagulation factors V and VIII is most common in specific Jewish populations. Genetic analysis mapped the responsible gene to chromosome 18, revealing potential founder effects.
Area of Science:
- Genetics
- Hematology
- Human Disease
Background:
- Combined deficiency of coagulation factor V and factor VIII is a rare autosomal recessive disorder.
- This condition is notably prevalent in specific populations, particularly Sephardic and Middle Eastern Jews in Israel.
Purpose of the Study:
- To identify the gene responsible for combined factors V and VIII deficiency using a positional cloning approach.
- To investigate the genetic origins and population distribution of this disorder.
Main Methods:
- Positional cloning strategy utilizing polymorphic genetic markers.
- Genome-wide analysis of 14 affected individuals from nine unrelated Jewish families.
- Haplotype analysis to infer genetic lineage and founder effects.
Main Results:
- The gene for combined factors V and VIII deficiency was successfully mapped to chromosome 18q.
- A maximal LOD score of 13.22 confirmed the linkage.
- Identification of two distinct haplotypes suggested either multiple founders or an ancient single founder.
Conclusions:
- The gene responsible for combined factors V and VIII deficiency has been localized to chromosome 18.
- Genetic analysis provides insights into the population genetics of this disorder.
- Further research on the identified gene will elucidate the biosynthesis of homologous coagulation factors.
Abstract:
Combined deficiency of coagulation factor V and factor VIII is an autosomal recessive disorder which has been observed in a number of populations around the world. However, this disease appears to be most common in the Mediterranean basin, particularly in Jews of Sephardic and Middle Eastern origin living in Israel. We have taken a positional cloning approach toward identifying the gene responsible for this disorder. We initially studied 14 affected individuals from nine unrelated Jewish families using a panel of polymorphic genetic markers spaced throughout the human genome. The combined factors V and VIII deficiency gene was mapped to a locus on the long arm of chromosome 18 with a maximal LOD score of 13.22. A detailed genetic analysis identified two distinct haplotypes among these families, suggesting two independent founders or, alternatively, a single ancient founder with a more recent split of these subpopulations. Further work to identify and characterize the gene responsible for combined factors V and VIII deficiency should provide important insights into the biosynthesis of these homologous proteins.