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Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm
Sandy Elbitar1,2, Marjolijn Renard3, Pauline Arnaud1,4,5
1Laboratory for Vascular Translational Science, INSERM U1148, Université de Paris, Centre Hospitalo-Universitaire Xavier Bichat, APHP, Paris, France.
Summary
Genetic variants in THSD4 are linked to thoracic aortic aneurysm and dissection (TAAD). This discovery improves understanding of TAAD and may lead to new therapies for this serious inherited condition.
Area of Science:
- Genetics
- Cardiovascular Biology
- Molecular Medicine
Background:
- Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition.
- Inherited forms of TAAD are often not recognized.
- Identifying genetic causes is crucial for diagnosis and treatment.
Purpose of the Study:
- To identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD.
- To investigate the role of specific genes in TAAD pathogenesis.
Main Methods:
- Exome sequencing of 35 French TAAD families.
- Next-generation sequencing panel on 1114 unrelated TAAD patients.
- Functional validation in cellular, tissue, and mouse models.
Main Results:
- Five functional variants in THSD4 were identified, two causing premature termination codons.
- THSD4 encodes ADAMTSL6, a protein vital for fibrillin-1 matrix assembly.
- THSD4 variants led to haploinsufficiency, impaired microfibril assembly, and progressive thoracic aorta dilation in mice.
- Histology revealed medial degeneration and extracellular matrix disruption in patients and mice.
Conclusions:
- ADAMTSL6 plays a significant role in aortic physiology and TAAD development.
- These findings can enhance TAAD management strategies.
- The study may facilitate the development of novel targeted therapies for TAAD.
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