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	Mathieu Barbier, Marie-Sylvie Gross, Mélodie Aubart, Nadine Hanna, Ketty Kessler, Dong-Chuan Guo, Laurent Tosolini, Benoit Ho-Tin-Noe, Ellen Regalado, Mathilde Varret, Marianne Abifadel, Olivier Milleron, Sylvie Odent, Sophie Dupuis-Girod, Laurence Faivre, Thomas Edouard, Yves Dulac, Tiffany Busa, Laurent Gouya, Dianna M Milewicz, Guillaume Jondeau, Catherine Boileau
Journal	American journal of human genetics (Am J Hum Genet) Vol. 95 Issue 6 Pg. 736-43 (Dec 04 2014) ISSN: 1537-6605 [Electronic] United States
PMID	25434006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Chemical References	Codon, Nonsense Contractile Proteins Glycoproteins Intercellular Signaling Peptides and Proteins MFAP5 protein, human
Topics	Adolescent Adult Aged Aged, 80 and over Amino Acid Substitution Aortic Dissection (genetics, physiopathology) Aortic Aneurysm, Thoracic (genetics, physiopathology) Child Codon, Nonsense Contractile Proteins (genetics, metabolism) Exome (genetics) Female Fibroblasts Glycoproteins (genetics, metabolism) Haploinsufficiency (genetics) Humans Intercellular Signaling Peptides and Proteins Male Middle Aged Pedigree Sequence Analysis, DNA

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