title: Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans.
abstract: Thoracic aortic aneurysms and dissections (TAAD) represent a substantial cause of morbidity and mortality worldwide. Many individuals presenting with an inherited form of TAAD do not have causal mutations in the set of genes known to underlie disease. Using whole-genome sequencing in two first cousins with TAAD, we identified a missense mutation in the lysyl oxidase (LOX) gene (c.893T > G encoding p.Met298Arg) that cosegregated with disease in the family. Using clustered regularly interspaced short palindromic repeats (CRISPR)/clustered regularly interspaced short palindromic repeats-associated protein-9 nuclease (Cas9) genome engineering tools, we introduced the human mutation into the homologous position in the mouse genome, creating mice that were heterozygous and homozygous for the human allele. Mutant mice that were heterozygous for the human allele displayed disorganized ultrastructural properties of the aortic wall characterized by fragmented elastic lamellae, whereas mice homozygous for the human allele died shortly after parturition from ascending aortic aneurysm and spontaneous hemorrhage. These data suggest that a missense mutation in LOX is associated with aortic disease in humans, likely through insufficient cross-linking of elastin and collagen in the aortic wall. Mutation carriers may be predisposed to vascular diseases because of weakened vessel walls under stress conditions. LOX sequencing for clinical TAAD may identify additional mutation carriers in the future. Additional studies using our mouse model of LOX-associated TAAD have the potential to clarify the mechanism of disease and identify novel therapeutics specific to this genetic cause.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Vivian S
authors.initials: VS
authors.lastname: Lee
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; Division of Nephrology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Halabi
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Erin P
authors.initials: EP
authors.lastname: Hoffman
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115; Harvard Medical School, Boston, MA 02115;
authors.forename: Nikkola
authors.initials: N
authors.lastname: Carmichael
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115; Harvard Medical School, Boston, MA 02115;
authors.forename: Ignaty
authors.initials: I
authors.lastname: Leshchiner
authors.affiliation: Harvard Medical School, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Christine G
authors.initials: CG
authors.lastname: Lian
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bierhals
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115; Harvard Medical School, Boston, MA 02115;
authors.forename: Dana
authors.initials: D
authors.lastname: Vuzman
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115; Harvard Medical School, Boston, MA 02115; VA Boston Healthcare System, Boston, MA 02132; nfrank@partners.org nstitziel@wustl.edu.
authors.forename: Natasha Y
authors.initials: NY
authors.lastname: Frank
authors.affiliation: Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110 nfrank@partners.org nstitziel@wustl.edu.
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Stitziel
mesh_terms: D000328:Adult; D000368:Aged; D000784:Aortic Dissection / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000201:enzymology / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D000073658:Loss of Function Mutation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010375:Pedigree; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D008249:Protein-Lysine 6-Oxidase
keywords: CRISPR/Cas9; aortic dissection; genetics; lysyl oxidase; whole-genome sequencing