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

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Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-08-28 , 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 _{1,

4,

5} , Marianne Abifadel _{1,

2}

Affiliation

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

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.

中文翻译：

编码 ADAMTS 样 6 蛋白的 THSD4 致病性变异易患遗传性胸主动脉瘤。

目的

胸主动脉瘤和夹层 (TAAD) 是一种威胁生命的疾病，其遗传形式通常无法识别。我们试图确定与 TAAD 的常染色体显性遗传相关的新致病变异。

方法

我们分析了来自 35 个法国 TAAD 家族的外显子组测序数据，并对 1114 名无关 TAAD 患者进行了下一代基因测序捕获面板。在细胞、组织和小鼠模型中验证了鉴定的致病变异的功能影响。

结果

我们在THSD4中鉴定了五个功能变体，其中两个杂合变体导致过早终止密码子。THSD4编码 ADAMTSL6（ADAMTS/L 超家族成员），这是一种促进原纤维蛋白-1 基质组装的微原纤维相关蛋白。研究的THSD4变体导致原纤维蛋白 1 微纤维的单倍体不足或组装受损。Thsd4 ^+/-小鼠表现出胸主动脉进行性扩张。来自携带THSD4变体的患者和来自Thsd4 ^+/-小鼠的主动脉样本的组织学检查显示典型的中层变性和细胞外基质的弥漫性破坏。