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.

Genome editing for the reproduction and remedy of human diseases in mice

“…Lee et al [19] carried out exome-sequencing analysis of patients with familial thoracic aortic aneurysms and dissections (FTAAD) to identify a causal mutation of the disease. They finally identified a missense mutation at the LOX gene (p.M298R) as a strong candidate for FTAAD.…”

Notch1 haploinsufficiency causes ascending aortic aneurysms in mice

“…TAAs are typically found in associated syndromic populations including Marfan syndrome (MFS), caused by mutations in FBN1 (3-6); Loeys-Deitz syndrome, caused by mutations in TGFBR1, TGFBR2, TGFB2, TGFB3, and SMAD3 (7-10); Fabry disease, caused by mutations in GLA (11); Turner syndrome, associated with monsomy of chromosome X (12); and Ehlers-Danlos syndrome, caused by mutations in Col3A1 (13). Additional genetic links to TAA have also been reported in families harboring diseasesegregating mutations in ACTA2 (14), MYH11 (15), LOX (16,17), and FOXE3 (18).…”

Mechanical behavior and matrisome gene expression in the aneurysm-prone thoracic aorta of newborn lysyl oxidase knockout mice

“…Mice that do not express lysyl oxidase (Lox Ϫ/Ϫ ) have fragmented elastic fibers in the arteries, lungs, and skin and die within a few hours of birth with a ruptured diaphragm, impaired airway development, and thoracic aortic aneurysm and dissection (TAAD) (19,31,32). Recently, point mutations in LOX have been linked to TAAD in humans (16,27).…”