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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.

"When a patient comes to the clinic with an enlarged aorta, clinicians can evaluate a standard list of genes to look for a cause of the condition," senior author Nathan Stitziel from WashU said in a statement. "Lysyl oxidase should now be added to the standard test panel. This type of information can provide clarity for families with histories of unexplained aortic aneurysms."

In this study, the proband was a 35-year-old white man who'd undergone surgical repair of a sunken breastbone as a toddler and who was diagnosed with a large ascending aortic aneurysm at age 19, after which he underwent valve-sparing aortic root replacement.

While the proband was suspected to have Marfan syndrome based on his clinical presentation, genetic testing of Marfan-linked genes like FBN1 and TGFBR1 came up empty. His mother, who also had a history of acute ascending aortic dissection, underwent genetic testing, though it too was unable to uncover a causal variant for her. Still, the researchers noted that their family history suggested an autosomal dominant disorder.

Stitziel and his colleagues performed whole-genome sequencing of the proband and his first cousin, who also had a history of disease. To home in on putative causal mutations, the researchers restricted their search to ones that were heterozygous in the cousins, that were rare, and that had a functional effect on the gene product. This left them with a missense substitution in LOX.

As LOX is known to be involved in arterial wall biology, the researchers deemed it to be a strong candidate gene. LOX is a copper-binding enzyme that catalyzes the cross-linking of collagen and elastin, and this substitution, which occurs at a highly conserved locus, falls within the copper-binding domain, suggesting that the mutation might affect LOX function.

"The layers and fibers of the aorta are almost like the belts inside a tire," Stitziel said. "You have to have the right structure to maintain the strength and integrity of the artery. Lysyl oxidase cross-links the fibers together. When there is less lysyl oxidase than there should be, the proper structure is disrupted."

Using a CRISPR/Cas9 genome editing approach, Stitziel and his colleagues introduced this mutation into the homologous site in the mouse genome. While mice heterozygous for the mutation appeared largely normal, they had an ascending aortic length that was 10 percent larger than that of their wild-type littermates and stiffer carotid and ascending aorta at higher pressure, suggesting that the heterozygous animals had affected vessel walls.

Meanwhile, mice homozygous for the mutation only lived a few hours. According to the researchers, these mice had tortuous vessels with aneurysms in the ascending aorta and the aortic arch. They also had aneurysms in the descending abdominal aorta.

Through gene array analysis, the researchers also noted that all Lox family members are expressed in the developing aorta, though the missense mutation doesn't lead to decreased mRNA expression or protein synthesis. However, the missense mutation does affect Lox enzymatic activity, the researchers reported.

This, Stitziel and his colleagues said, indicates that the LOX missense mutation causes aortic aneurysm and dissection because of inadequate cross-linking of collagen and elastin in the aortic wall. It further could be both a diagnostic and therapeutic target, they added, noting that their mouse model could help clarify disease pathogenesis and uncover treatment approaches.