American journal of human genetics

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

PMID 25434006


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.