Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm PMID: 32855533

Target-related Cytokines

2026-09-23

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm

Genet Med. 2021 Jan;23(1):111-122. doi: 10.1038/s41436-020-00947-4.

Sandy Elbitar ^# ¹ ² , Marjolijn Renard ^# ³ , Pauline Arnaud ¹ ⁴ ⁵ , Nadine Hanna ¹ ⁴ ⁵ , Marie-Paule Jacob ¹ , Dong-Chuan Guo ⁶ , Ko Tsutsui ⁷ , Marie-Sylvie Gross ¹ , Ketty Kessler ⁸ , Laurent Tosolini ¹ , Vincenzo Dattilo ⁹ , Sebastien Dupont ¹ , Jeremie Jonquet ¹ , Maud Langeois ⁵ , Louise Benarroch ¹ ¹⁰ , Melodie Aubart ¹ ¹¹ , Youmna Ghaleb ¹ ² , Yara Abou Khalil ¹ ² , Mathilde Varret ¹ , Petra El Khoury ¹ ² , Benoit Ho-Tin-Noé ¹ , Yves Alembik ¹² , Sébastien Gaertner ¹³ , Bertrand Isidor ¹⁴ , Laurent Gouya ⁵ , Olivier Milleron ⁵ , Kiyotoshi Sekiguchi ⁷ , Dianna Milewicz ⁶ , Julie De Backer ³ , Carine Le Goff ¹ , Jean-Baptiste Michel ¹ , Guillaume Jondeau ¹ ⁵ , Lynn Y Sakai ¹⁵ , Catherine Boileau ^# ¹⁶ ¹⁷ ¹⁸ , Marianne Abifadel ^# ¹⁹ ²⁰

Affiliations

1. Laboratory for Vascular Translational Science, INSERM U1148, Université de Paris, Centre Hospitalo-Universitaire Xavier Bichat, APHP, Paris, France.
2. Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie-Santé, Saint Joseph University of Beirut, Beirut, Lebanon.
3. Center for Medical Genetics, Ghent University, Ghent, Belgium.
4. Département de Génétique, Centre Hospitalo-Universitaire Xavier Bichat, APHP, Paris, France.
5. Hospitalo-Universitaire Xavier Bichat, APHP, Centre de Référence Maladies Rares, Syndrome de Marfan et pathologies apparentées, Paris, France.
6. Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
7. Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
8. Centre for Evolution and Cancer, Division of Molecular Pathology, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
9. IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
10. Inserm UMRS_974, Centre de recherche en myologie, G.H. Pitié-Salpétrière, APHP, Paris, France.
11. Service de Neuropédiatrie, Hôpital Necker-Enfants-Malades, APHP, Paris, France.
12. Department of Clinical Genetic, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
13. Department of Hypertension, Vascular Diseases and Pharmacology, University of Strasbourg, Strasbourg, France.
14. Service de Génétique Médicale, Hôpital Hôtel-Dieu, Centre Hospitalier Universitaire de Nantes, Nantes, France.
15. Shriners Hospital for Children, Molecular & Medical Genetics and Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, OR, USA.
16. Laboratory for Vascular Translational Science, INSERM U1148, Université de Paris, Centre Hospitalo-Universitaire Xavier Bichat, APHP, Paris, France. [email protected].
17. Département de Génétique, Centre Hospitalo-Universitaire Xavier Bichat, APHP, Paris, France. [email protected].
18. Hospitalo-Universitaire Xavier Bichat, APHP, Centre de Référence Maladies Rares, Syndrome de Marfan et pathologies apparentées, Paris, France. [email protected].
19. Laboratory for Vascular Translational Science, INSERM U1148, Université de Paris, Centre Hospitalo-Universitaire Xavier Bichat, APHP, Paris, France. [email protected].
20. Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie-Santé, Saint Joseph University of Beirut, Beirut, Lebanon. [email protected].
# Contributed equally.

Abstract

Purpose: Thoracic Aortic Aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD.

Methods: We analyzed exome Sequencing data from 35 French TAAD families and performed next-generation Sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models.

Results: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4^+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4^+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.

Conclusion: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.

Keywords

ADAMTSL6; THSD4; diagnosis; thoracic aortic aneurysm.