title: NOTCH1 Mutations in Aortic Stenosis: Association with Osteoprotegerin/RANK/RANKL.
abstract: Background. The NOTCH pathway is known to be important in the pathogenesis of calcific aortic valve disease, possibly through regulators of osteoprotegerin (OPG), receptor activator of nuclear factorκB (RANK), and its ligand (RANKL) system. Thepurposeof the present study was to search for possible associations betweenNOTCH1gene mutations and circulating levels of OPG and soluble RANKL (sRANKL) in patients with aortic stenosis (AS).Methods. The study was performed on 61 patients with AS including 31 with bicuspid and 30 with tricuspid aortic valves. We applied a strategy of targeted mutation screening for 10 out of 34 exons of theNOTCH1gene by direct sequencing. Serum OPG and sRANKL levels were assessed.Results. In total, 6 genetic variants of theNOTCH1gene including two new mutations were identified in the study group. In an age- and arterial hypertension-adjusted multivariable regression analysis, the serum OPG levels and the OPG/sRANKL ratio were correlated withNOTCH1missense variants. All studied missense variants in NOTCH1 gene were found in Ca(2+)-binding EGF motif of the NOTCH extracellular domain bound to Delta-like 4.Conclusion. Our results suggest that the OPG/RANKL/RANK system might be directly influenced by genetic variants of NOTCH1 in aortic valve calcification.
authors.affiliation: Federal Almazov Medical Research Centre, St. Petersburg, Russia; Institute of translational Medicine, ITMO University, St. Petersburg, Russia.
authors.forename: Olga
authors.identifier: 0000-0002-8656-3191
authors.initials: O
authors.lastname: Irtyuga
authors.affiliation: Federal Almazov Medical Research Centre, St. Petersburg, Russia; St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Anna
authors.identifier: 0000-0002-0820-2913
authors.initials: A
authors.lastname: Malashicheva
authors.affiliation: Federal Almazov Medical Research Centre, St. Petersburg, Russia.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Zhiduleva
authors.affiliation: Federal Almazov Medical Research Centre, St. Petersburg, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Freylikhman
authors.affiliation: Federal Almazov Medical Research Centre, St. Petersburg, Russia.
authors.forename: Oxana
authors.initials: O
authors.lastname: Rotar
authors.affiliation: Department of Medicine and Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus
authors.identifier: 0000-0003-0853-5141
authors.initials: M
authors.lastname: Bäck
authors.affiliation: St. Petersburg Polytechnic University, St. Petersburg, Russia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Tarnovskaya
authors.affiliation: Federal Almazov Medical Research Centre, St. Petersburg, Russia; Department of Woman and Child Health and Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Kostareva
authors.affiliation: Federal Almazov Medical Research Centre, St. Petersburg, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
mesh_terms: D000595:Amino Acid Sequence; D001024:Aortic Valve Stenosis / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D053244:Osteoprotegerin / Q000097:blood*; D000072417:Protein Domains; D053245:RANK Ligand / Q000097:blood*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012995:Solubility
chemical_list: C497761:NOTCH1 protein, human; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D051881:Receptor, Notch1