MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections

Am J Hum Genet. 2014 Dec 4;95(6):736-43. doi: 10.1016/j.ajhg.2014.10.018.

Mathieu Barbier ¹, Marie-Sylvie Gross ¹, Mélodie Aubart ¹, Nadine Hanna ², Ketty Kessler ¹, Dong-Chuan Guo ³, Laurent Tosolini ¹, Benoit Ho-Tin-Noe ¹, Ellen Regalado ³, Mathilde Varret ¹, Marianne Abifadel ¹, Olivier Milleron ⁴, Sylvie Odent ⁵, Sophie Dupuis-Girod ⁶, Laurence Faivre ⁷, Thomas Edouard ⁸, Yves Dulac ⁸, Tiffany Busa ⁹, Laurent Gouya ⁴, Dianna M Milewicz ³, Guillaume Jondeau ¹⁰, Catherine Boileau ¹¹

Affiliations

1 INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
2 INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France; AP-HP, Département de Génétique, Hôpital Bichat, 75018 Paris, France.
3 Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
4 AP-HP, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Hôpital Bichat, 75018 Paris, France; UFR de Médecine, Université Paris Diderot, 75018 Paris, France.
5 Service de Génétique Clinique, Hôpital Sud-CHU de Rennes, 35200 Rennes, France.
6 Service de Génétique clinique, Hôpital Louis Pradel, CHU de Lyon-GH Est, 69677 Bron, France.
7 Equipe GAD, EA 4271, Université de Bourgogne, 21000 Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, 21000 Dijon, France.
8 Pédiatrie - Endocrinologie, Génétique et Gynécologie médicale, Hôpital des enfants, CHU de Toulouse, 31059 Toulouse, France.
9 Département de Génétique médicale, Hôpital de la Timone, CHU de Marseille, 13005 Marseille, France.
10 INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France; AP-HP, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Hôpital Bichat, 75018 Paris, France; UFR de Médecine, Université Paris Diderot, 75018 Paris, France.
11 INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France; AP-HP, Département de Génétique, Hôpital Bichat, 75018 Paris, France; AP-HP, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Hôpital Bichat, 75018 Paris, France; UFR de Médecine, Université Paris Diderot, 75018 Paris, France. Electronic address: catherine.boileau@bch.aphp.fr.

PMID: 25434006 DOI: 10.1016/j.ajhg.2014.10.018

Abstract

Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome Sequencing of affected members in a large TAAD-affected family, we identified the c.472C>T (p.Arg158(∗)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62G>T [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.

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