Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans

Vivian S. Leea, Carmen M. Halabi, Erin P. Hoffman, Nikkola Carmichael, Ignaty Leshchiner, Christine G. Lian, Andrew J. Bierhals, Dana Vuzman, Brigham Genomic Medicine, Robert P. Mecham, Natasha Y. Frank, Nathan O. Stitziel

Research output: Contribution to journalArticle

59 Scopus citations

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 noveltherapeutics specific to this genetic cause.

Original languageEnglish
Pages (from-to)8759-8764
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number31
DOIs
StatePublished - Aug 2 2016

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