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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
A common mutation, Arg457-->Gln, links prothrombin deficiencies in the Puerto Rican population
J B Lefkowitz1, A Weller, R Nuss
1Department of Pathology, University of Colorado School of Medicine, Denver, Colorado 80262, USA. Jerry.Lefkowitz@UCHSC.edu
Journal of Thrombosis and Haemostasis : JTH
|November 25, 2003
Summary
Genetic prothrombin deficiency is common in Puerto Rico due to a founder effect. Researchers identified four novel mutations, including a common R457Q variant, causing bleeding disorders.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Prothrombin deficiency is a rare genetic bleeding disorder.
- It is the third most common congenital coagulation factor deficiency at the University of Puerto Rico Hemophilia Center.
- Puerto Rico's relative isolation suggests a potential founder effect for genetic disorders.
Observation:
- Five unrelated Puerto Rican families presented with bleeding due to prothrombin deficiency.
- Prothrombin genes from affected individuals and parents were sequenced.
- Four novel prothrombin mutations were identified.
Findings:
- A common G-->A substitution (R457Q) was found in all five families, with some individuals being homozygous.
- Three other mutations were identified: a point mutation (gamma16Q), a deletion, and a splice junction mutation.
- The R457Q mutation destabilizes prothrombin, leading to hypoprothrombinemia and dysprothrombinemia.
Implications:
- The identified mutations, particularly R457Q, contribute to the prevalence of prothrombin deficiency in Puerto Rico.
- Understanding these mutations aids in diagnosing and managing bleeding disorders in this population.
- The study highlights the importance of founder effects in the genetic landscape of rare diseases.
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