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Article

Genetic Variants in the Extracellular Matrix Gene TNXB Predicted to Alter Fibronectin III Domains in Arterial Aneurysmal and Dissection Diseases

by
Charlene Norgan Radler
1,†,
Tianci Wang
1,†,
Jaden LeGate
1,‡,
Lily Crone
1,‡,
Parminder Deo
1,
Jacob Wortley
1,
Peyton Moore
1,
Griffin Bryant
1,
Katherine Smitherman
1,2 and
Mohanakrishnan Sathyamoorthy
1,3,4,*
1
Sathyamoorthy Laboratory, Department of Medicine, Anne Burnett Marion School of Medicine at TCU, Fort Worth, TX 76104, USA
2
College of Arts and Sciences, Cornell University, Ithaca, NY 14850, USA
3
Consultants in Cardiovascular Medicine and Science, Fort Worth, TX 76104, USA
4
Fort Worth Institute for Molecular Medicine and Genomics Research, Fort Worth, TX 76104, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(13), 6535; https://doi.org/10.3390/ijms26136535
Submission received: 2 March 2025 / Revised: 18 June 2025 / Accepted: 3 July 2025 / Published: 7 July 2025
(This article belongs to the Special Issue Genes and Human Diseases 2.0)
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Abstract

Arterial aneurysms are vascular conditions associated with life-threatening consequences in patients, such as dissection and rupture. Understanding their genetic basis is an evolving field, driven by the robust reporting of genetic variants associated with aneurysms in patients. In this study, we present clinical and genetic data from nine unrelated subjects with arterial aneurysms who were identified to harbor rare variants in the TNXB gene, mainly affecting fibronectin type III (FNIII) domains. The cohort included three female and six male subjects with a mean age of 53.5 years (SD = 14.4). The most frequently affected vascular territory was the thoracic ascending aorta (n = 7). A range of pathogenic impacts was predicted via multiple in silico tools that analyze evolutionary conservation and biochemical properties. Computational protein structure modeling with AlphaFold 3 predicted domain-specific alterations across multiple FNIII regions for four unique missense variants and one in-frame deletion, and premature protein truncation resulting from two frameshift variants. To our knowledge, this study is one of the first and largest to associate TNXB variants with arterial aneurysmal disease. Our findings demonstrate the potential of computational genomics and structural modeling to advance the understanding of extracellular matrix gene alterations in aneurysm pathogenesis.
Keywords: TNXB; aortic aneurysm; carotid aneurysm; splenic aneurysm; arteriovenous malformation; bicuspid aortic valve; extracellular matrix; collagen matrix protein; fibronectin; genetic; single nucleotide variant; frameshift variant; AlphaFold TNXB; aortic aneurysm; carotid aneurysm; splenic aneurysm; arteriovenous malformation; bicuspid aortic valve; extracellular matrix; collagen matrix protein; fibronectin; genetic; single nucleotide variant; frameshift variant; AlphaFold

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MDPI and ACS Style

Norgan Radler, C.; Wang, T.; LeGate, J.; Crone, L.; Deo, P.; Wortley, J.; Moore, P.; Bryant, G.; Smitherman, K.; Sathyamoorthy, M. Genetic Variants in the Extracellular Matrix Gene TNXB Predicted to Alter Fibronectin III Domains in Arterial Aneurysmal and Dissection Diseases. Int. J. Mol. Sci. 2025, 26, 6535. https://doi.org/10.3390/ijms26136535

AMA Style

Norgan Radler C, Wang T, LeGate J, Crone L, Deo P, Wortley J, Moore P, Bryant G, Smitherman K, Sathyamoorthy M. Genetic Variants in the Extracellular Matrix Gene TNXB Predicted to Alter Fibronectin III Domains in Arterial Aneurysmal and Dissection Diseases. International Journal of Molecular Sciences. 2025; 26(13):6535. https://doi.org/10.3390/ijms26136535

Chicago/Turabian Style

Norgan Radler, Charlene, Tianci Wang, Jaden LeGate, Lily Crone, Parminder Deo, Jacob Wortley, Peyton Moore, Griffin Bryant, Katherine Smitherman, and Mohanakrishnan Sathyamoorthy. 2025. "Genetic Variants in the Extracellular Matrix Gene TNXB Predicted to Alter Fibronectin III Domains in Arterial Aneurysmal and Dissection Diseases" International Journal of Molecular Sciences 26, no. 13: 6535. https://doi.org/10.3390/ijms26136535

APA Style

Norgan Radler, C., Wang, T., LeGate, J., Crone, L., Deo, P., Wortley, J., Moore, P., Bryant, G., Smitherman, K., & Sathyamoorthy, M. (2025). Genetic Variants in the Extracellular Matrix Gene TNXB Predicted to Alter Fibronectin III Domains in Arterial Aneurysmal and Dissection Diseases. International Journal of Molecular Sciences, 26(13), 6535. https://doi.org/10.3390/ijms26136535

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