A rare variant in MCF2L identified using exclusion linkage in a pedigree with premature atherosclerosis
| Autor: | Stephanie Maiwald, Suthesh Sivapalaratnam, G. Kees Hovingh, Geesje M. Dallinga-Thie, M. Mahdi Motazacker, John J.P. Kastelein, Jaap D. van Buul, Allard C. van der Wal, Julian C. van Capelleveen, Chris M. van der Loos, Mieke D. Trip, Willem H. Ouwehand |
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| Přispěvatelé: | Other departments, Amsterdam Cardiovascular Sciences, Human Genetics, Vascular Medicine, Graduate School, Pathology, Cardiology, Landsteiner Laboratory |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Adult
Male rac1 GTP-Binding Protein 0301 basic medicine RHOA Genetic Linkage Molecular Sequence Data RAC1 Disease 030204 cardiovascular system & hematology Biology Transfection Article Cohort Studies 03 medical and health sciences 0302 clinical medicine Genetic linkage Genetics Humans Rare functional variant Age of Onset Genetics (clinical) Cause of death Base Sequence Molecular pathology Middle Aged Atherosclerosis Plaque Atherosclerotic Pedigree 030104 developmental biology Gene Expression Regulation Mutation biology.protein Female Guanine nucleotide exchange factor rhoA GTP-Binding Protein Rho Guanine Nucleotide Exchange Factors HeLa Cells Plasmids Protein Binding Signal Transduction |
| Zdroj: | European journal of human genetics, 24(1), 86-91. Nature Publishing Group |
| ISSN: | 1018-4813 |
| DOI: | 10.1038/ejhg.2015.70 |
| Popis: | Cardiovascular disease (CVD) is a major cause of death in Western societies. CVD risk is largely genetically determined. The molecular pathology is, however, not elucidated in a large number of families suffering from CVD. We applied exclusion linkage analysis and next-generation sequencing to elucidate the molecular defect underlying premature CVD in a small pedigree, comprising two generations of which six members suffered from premature CVD. A total of three variants showed co-segregation with the disease status in the family. Two of these variants were excluded from further analysis based on the prevalence in replication cohorts, whereas a non-synonymous variant in MCF.2 Cell Line Derived Transforming Sequence-like protein (MCF2L, c.2066A>G; p.(Asp689Gly); NM_001112732.1), located in the DH domain, was only present in the studied family. MCF2L is a guanine exchange factor that potentially links pathways that signal through Rac1 and RhoA. Indeed, in HeLa cells, MCF2L689Gly failed to activate Rac1 as well as RhoA, resulting in impaired stress fiber formation. Moreover, MCF2L protein was found in human atherosclerotic lesions but not in healthy tissue segments. In conclusion, a rare functional variant in MCF2L, leading to impaired DH function, was identified in a small pedigree with premature CVD. The presence of MCF2L in human atherosclerotic plaque specimen lends further support to its potential role in atherosclerosis. |
| Databáze: | OpenAIRE |
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