title: MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections.
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.
authors.affiliation: INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Barbier
authors.affiliation: INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
authors.forename: Marie-Sylvie
authors.initials: MS
authors.lastname: Gross
authors.affiliation: INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
authors.forename: Mélodie
authors.initials: M
authors.lastname: Aubart
authors.affiliation: 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.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hanna
authors.affiliation: INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
authors.forename: Ketty
authors.initials: K
authors.lastname: Kessler
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Dong-Chuan
authors.initials: DC
authors.lastname: Guo
authors.affiliation: INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Tosolini
authors.affiliation: INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Ho-Tin-Noe
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Regalado
authors.affiliation: INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
authors.affiliation: INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Milleron
authors.affiliation: Service de Génétique Clinique, Hôpital Sud-CHU de Rennes, 35200 Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.affiliation: Service de Génétique clinique, Hôpital Louis Pradel, CHU de Lyon-GH Est, 69677 Bron, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dupuis-Girod
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Pédiatrie - Endocrinologie, Génétique et Gynécologie médicale, Hôpital des enfants, CHU de Toulouse, 31059 Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Edouard
authors.affiliation: Pédiatrie - Endocrinologie, Génétique et Gynécologie médicale, Hôpital des enfants, CHU de Toulouse, 31059 Toulouse, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dulac
authors.affiliation: Département de Génétique médicale, Hôpital de la Timone, CHU de Marseille, 13005 Marseille, France.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Busa
authors.affiliation: 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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
authors.affiliation: 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.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jondeau
authors.affiliation: 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.
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000784:Aortic Dissection / Q000235:genetics* / Q000503:physiopathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D018389:Codon, Nonsense; D003285:Contractile Proteins / Q000235:genetics* / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense; D003285:Contractile Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C115627:MFAP5 protein, human