MFAP5 Loss-of-Function Mutations Underscore the Involvement of Matrix Alteration in the Pathogenesis of Familial Thoracic Aortic Aneurysms and Dissections

6533b85dfe1ef96bd12be008

RESEARCH PRODUCT

MFAP5 Loss-of-Function Mutations Underscore the Involvement of Matrix Alteration in the Pathogenesis of Familial Thoracic Aortic Aneurysms and Dissections

Mathilde Varret Ketty Kessler Laurent Tosolini Thomas Edouard Dongchuan Guo Ellen S. Regalado Laurence Faivre Marie Sylvie Gross Mathieu Barbier Benoît Ho-tin-noé Yves Dulac Marianne Abifadel Sophie Dupuis-girod Olivier Milleron Sylvie Odent Guillaume Jondeau Mélodie Aubart Nadine Hanna Laurent Gouya Dianna M. Milewicz Catherine Boileau Tiffany Busa

subject

Adult Male congenital hereditary and neonatal diseases and abnormalities Adolescent Extracellular matrix component Nonsense mutation Haploinsufficiency Thoracic aortic aneurysm Pathogenesis Contractile Proteins Report Genetics medicine Humans Missense mutation Genetics(clinical)Exome Child Genetics (clinical)Aged Glycoproteins Aged 80 and over Genetics Aortic Aneurysm Thoracic biology Genetic heterogeneity Sequence Analysis DNA Fibroblasts Middle Aged medicine.disease Pedigree 3. Good health Aortic Dissection Amino Acid Substitution Codon Nonsense biology.protein Intercellular Signaling Peptides and Proteins Female Haploinsufficiency Elastin

description

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.472CT (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.62GT [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.

year	journal	country	edition	language
2014-12-01	The American Journal of Human Genetics

10.1016/j.ajhg.2014.10.018 http://dx.doi.org/10.1016/j.ajhg.2014.10.018