Lysyl Oxidase (LOX) gene missense mutation causes Thoracic Aortic Aneurysm and Dissection (TAAD) in Humans because of inadequate cross-linking of collagen and elastin in the aortic wall
Mutation carriers may be predisposed to vascular diseases because of weakened vessel walls under stress conditions.
Reporting: Aviva Lev-Ari, PhD, RN
Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans
- Vivian S. Leea,
- Carmen M. Halabia,b,
- Erin P. Hoffmanc,1,
- Nikkola Carmichaelc,d,
- Ignaty Leshchinerc,d,
- Christine G. Liand,e,
- Andrew J. Bierhalsf,
- Dana Vuzmanc,d,
- Brigham Genomic Medicine2,
- Robert P. Mechama,
- Natasha Y. Frankc,d,g,3, and
- Nathan O. Stitzielh,i,j,3
Edited by J. G. Seidman, Harvard Medical School, Boston, MA, and approved June 7, 2016 (received for review January 27, 2016)
↵1Present address: Department of Oncology, Littleton Adventist Hospital, Littleton, CO 80122.
- 3To whom correspondence may be addressed. Email: firstname.lastname@example.org or email@example.com.
Author contributions: V.S.L., R.P.M., N.Y.F., and N.O.S. designed research; V.S.L., C.M.H., and N.O.S. performed research; E.P.H., N.C., C.G.L., D.V., B.G.M.P., R.P.M., and N.Y.F. contributed new reagents/analytic tools; V.S.L., C.M.
The mechanical integrity of the arterial wall is dependent on a properly structured ECM. Elastin and collagen are key structural components of the ECM, contributing to the stability and elasticity of normal arteries. Lysyl oxidase (LOX) normally cross-links collagen and elastin molecules in the process of forming proper collagen fibers and elastic lamellae. Here, using whole-genome sequencing in humans and genome engineering in mice, we show that a missense mutation in LOX causes aortic aneurysm and dissection because of insufficient elastin and collagen cross-linking in the aortic wall. These findings confirm mutations in LOX as a cause of aortic disease in humans and identify LOX as a diagnostic and potentially therapeutic target.
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.
Missense LOX Mutation Linked to Aortic Rupture, Aneurysm
NEW YORK (GenomeWeb) – Researchers from Washington University School of Medicine have linked a LOX gene variant with aortic rupture and aneurysm.
As they reported in the online early edition of the Proceedings of the National Academy of Sciences yesterday, the researchers sequenced two first cousins from a family with a history of aortic ruptures and aneurysms to uncover a missense mutation in the lysyl oxidase (LOX) gene, which encodes a protein that cross-links elastin and collagen. When they used CRISPR/Cas9 genome engineering to introduce the mutation into a mouse model, mice heterogeneous for the mutation had disorganized aortic walls, while mice homozygous for the mutation died shortly after birth of ascending aneurysm and spontaneous hemorrhage, suggesting that the LOX variant might be causal.
Read more @ the Source