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Published on: May 16, 2025
LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.
Dong-chuan Guo1, Ellen S Regalado1, Limin Gong1
1From the Departments of Internal Medicine (D.G., E.S.R., L.G., X.D., Z.R., B.C., E.M.H., D.M.M.) and Cardiothoracic and Vascular Surgery (A.E., H.J.S.), University of Texas Health Science Center, Houston; Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX (R.L.P.S.-C., S.M.L.); Laboratory for Vascular Translational Science, INSERM U1148, Hôpital Bichat, Paris, France (P.A., G.J., C.B.); Centre National de Référence pour le syndrome de Marfan et apparentés, Département de Génétique Moléculaire, AP-HP, Hôpital Bichat, Paris, France (P.A., C.B.); Department of Pediatrics, MetroHealth Medical Center, Cleveland, OH (R.M.); Department of Medicine, Stanford University Medical Center, CA (D.L.); and Department of Genome Sciences, University of Washington, Seattle (M.J.B., J.S., D.A.N.).
Genetic variants in the LOX gene are linked to thoracic aortic aneurysms and dissections. These LOX mutations impair lysyl oxidase activity, increasing predisposition to aortic disease.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Molecular Biology
Background:
- Familial thoracic aortic aneurysms and dissections (TAAD) are heritable conditions.
- While 25% of TAAD cases are linked to known genes, the genetic cause for the remaining 75% remains elusive.
- Identifying novel causative genes is crucial for understanding TAAD pathogenesis and developing targeted therapies.
Purpose of the Study:
- To identify the causative genetic mutation in families with autosomal dominant inheritance of TAAD.
- To investigate the role of the lysyl oxidase (LOX) gene in the etiology of TAAD.
Main Methods:
- Whole-exome sequencing was employed to identify genetic variants in a large family with TAAD.
- Segregation analysis and Sanger sequencing were used to validate LOX variants in additional families.
- Functional assays were performed to assess the impact of identified LOX variants on enzyme activity.
Main Results:
- A heterozygous rare variant (c.839G>T, p.Ser280Arg) in the LOX gene was identified and segregated with TAAD in the index family.
- Additional disease-segregating rare variants in LOX were found in 410 unrelated probands, including loss-of-function variants.
- LOX variants significantly reduced lysyl oxidase activity and were associated with aortic root and ascending aorta enlargement, leading to dissections.
Conclusions:
- Rare genetic variants in the LOX gene predispose individuals to thoracic aortic disease.
- LOX deficiency or impaired lysyl oxidase activity is mechanistically linked to aortic dissections.
- These findings expand the genetic basis of TAAD and highlight LOX as a key player in aortic wall integrity.
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