title: A rare variant in MCF2L identified using exclusion linkage in a pedigree with premature atherosclerosis.
abstract: 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.
authors.affiliation: Departments of Vascular and Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Maiwald
authors.affiliation: Departments of Vascular and Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Mahdi M
authors.initials: MM
authors.lastname: Motazacker
authors.affiliation: Departments of Vascular and Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Julian C
authors.initials: JC
authors.lastname: van Capelleveen
authors.affiliation: Departments of Vascular and Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Suthesh
authors.initials: S
authors.lastname: Sivapalaratnam
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: van der Loos
authors.affiliation: Departments of Vascular and Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, UK.|National Health service Blood and Transplant, Cambridge, UK.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Departments of Vascular and Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.affiliation: Departments of Vascular and Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.|Department of Cardiology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Mieke D
authors.initials: MD
authors.lastname: Trip
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jaap D
authors.initials: JD
authors.lastname: van Buul
authors.affiliation: Departments of Vascular and Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
mesh_terms: D000328:Adult; D017668:Age of Onset; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D011485:Protein Binding; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C577400:MCF2L protein, human; C107953:RAC1 protein, human; D064067:Rho Guanine Nucleotide Exchange Factors; C066737:RHOA protein, human; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein