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

Sandy Elbitar; Marjolijn Renard; Pauline Arnaud; Nadine Hanna; Marie Paule Jacob; Dong Chuan Guo; Ko Tsutsui; Marie Sylvie Gross; Ketty Kessler; Laurent Tosolini; Vincenzo Dattilo; Sebastien Dupont; Jeremie Jonquet; Maud Langeois; Louise Benarroch; Melodie Aubart; Youmna Ghaleb; Yara Abou Khalil; Mathilde Varret; Petra El Khoury; Benoit Ho-Tin-Noé; Yves Alembik; Sébastien Gaertner; Bertrand Isidor; Laurent Gouya; Olivier Milleron; Kiyotoshi Sekiguchi; Dianna Milewicz; Julie De Backer; Carine Le Goff; Jean Baptiste Michel; Guillaume Jondeau; Lynn Y. Sakai; Catherine Boileau; Marianne Abifadel

doi:10.1038/s41436-020-00947-4

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

Sandy Elbitar, Marjolijn Renard, Pauline Arnaud, Nadine Hanna, Marie Paule Jacob, Dong Chuan Guo, Ko Tsutsui, Marie Sylvie Gross, Ketty Kessler, Laurent Tosolini, Vincenzo Dattilo, Sebastien Dupont, Jeremie Jonquet, Maud Langeois, Louise Benarroch, Melodie Aubart, Youmna Ghaleb, Yara Abou Khalil, Mathilde Varret, Petra El KhouryBenoit Ho-Tin-Noé, Yves Alembik, Sébastien Gaertner, Bertrand Isidor, Laurent Gouya, Olivier Milleron, Kiyotoshi Sekiguchi, Dianna Milewicz, Julie De Backer, Carine Le Goff, Jean Baptiste Michel, Guillaume Jondeau, Lynn Y. Sakai, Catherine Boileau, Marianne Abifadel

Molecular and Medical Genetics

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English (US)
Pages (from-to)	111-122
Number of pages	12
Journal	Genetics in Medicine
Volume	23
Issue number	1
DOIs	https://doi.org/10.1038/s41436-020-00947-4
State	Published - Jan 2021

Keywords

ADAMTSL6
THSD4
diagnosis
thoracic aortic aneurysm

ASJC Scopus subject areas

Genetics(clinical)

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10.1038/s41436-020-00947-4

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Elbitar, S., Renard, M., Arnaud, P., Hanna, N., Jacob, M. P., Guo, D. C., Tsutsui, K., Gross, M. S., Kessler, K., Tosolini, L., Dattilo, V., Dupont, S., Jonquet, J., Langeois, M., Benarroch, L., Aubart, M., Ghaleb, Y., Abou Khalil, Y., Varret, M., ... Abifadel, M. (2021). Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm. Genetics in Medicine, 23(1), 111-122. https://doi.org/10.1038/s41436-020-00947-4

Elbitar, S, Renard, M, Arnaud, P, Hanna, N, Jacob, MP, Guo, DC, Tsutsui, K, Gross, MS, Kessler, K, Tosolini, L, Dattilo, V, Dupont, S, Jonquet, J, Langeois, M, Benarroch, L, Aubart, M, Ghaleb, Y, Abou Khalil, Y, Varret, M, El Khoury, P, Ho-Tin-Noé, B, Alembik, Y, Gaertner, S, Isidor, B, Gouya, L, Milleron, O, Sekiguchi, K, Milewicz, D, De Backer, J, Le Goff, C, Michel, JB, Jondeau, G, Sakai, LY, Boileau, C & Abifadel, M 2021, 'Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm', Genetics in Medicine, vol. 23, no. 1, pp. 111-122. https://doi.org/10.1038/s41436-020-00947-4

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

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",

author = "Sandy Elbitar and Marjolijn Renard and Pauline Arnaud and Nadine Hanna and Jacob, {Marie Paule} and Guo, {Dong Chuan} and Ko Tsutsui and Gross, {Marie Sylvie} and Ketty Kessler and Laurent Tosolini and Vincenzo Dattilo and Sebastien Dupont and Jeremie Jonquet and Maud Langeois and Louise Benarroch and Melodie Aubart and Youmna Ghaleb and {Abou Khalil}, Yara and Mathilde Varret and {El Khoury}, Petra and Benoit Ho-Tin-No{\'e} and Yves Alembik and S{\'e}bastien Gaertner and Bertrand Isidor and Laurent Gouya and Olivier Milleron and Kiyotoshi Sekiguchi and Dianna Milewicz and {De Backer}, Julie and {Le Goff}, Carine and Michel, {Jean Baptiste} and Guillaume Jondeau and Sakai, {Lynn Y.} and Catherine Boileau and Marianne Abifadel",

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year = "2021",

month = jan,

doi = "10.1038/s41436-020-00947-4",

language = "English (US)",

volume = "23",

pages = "111--122",

journal = "Genetics in Medicine",

issn = "1098-3600",

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TY - JOUR

T1 - Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm

AU - Elbitar, Sandy

AU - Renard, Marjolijn

AU - Arnaud, Pauline

AU - Hanna, Nadine

AU - Jacob, Marie Paule

AU - Guo, Dong Chuan

AU - Tsutsui, Ko

AU - Gross, Marie Sylvie

AU - Kessler, Ketty

AU - Tosolini, Laurent

AU - Dattilo, Vincenzo

AU - Dupont, Sebastien

AU - Jonquet, Jeremie

AU - Langeois, Maud

AU - Benarroch, Louise

AU - Aubart, Melodie

AU - Ghaleb, Youmna

AU - Abou Khalil, Yara

AU - Varret, Mathilde

AU - El Khoury, Petra

AU - Ho-Tin-Noé, Benoit

AU - Alembik, Yves

AU - Gaertner, Sébastien

AU - Isidor, Bertrand

AU - Gouya, Laurent

AU - Milleron, Olivier

AU - Sekiguchi, Kiyotoshi

AU - Milewicz, Dianna

AU - De Backer, Julie

AU - Le Goff, Carine

AU - Michel, Jean Baptiste

AU - Jondeau, Guillaume

AU - Sakai, Lynn Y.

AU - Boileau, Catherine

AU - Abifadel, Marianne

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

KW - ADAMTSL6

KW - THSD4

KW - diagnosis

KW - thoracic aortic aneurysm

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DO - 10.1038/s41436-020-00947-4

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SN - 1098-3600

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JO - Genetics in Medicine

JF - Genetics in Medicine

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

Abstract

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