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. Epub 2014 Nov 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Substitution
  • Aneurysm, Dissecting / genetics*
  • Aneurysm, Dissecting / physiopathology
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Aneurysm, Thoracic / physiopathology
  • Child
  • Codon, Nonsense
  • Contractile Proteins / genetics*
  • Contractile Proteins / metabolism
  • Exome / genetics
  • Female
  • Fibroblasts
  • Glycoproteins / genetics*
  • Glycoproteins / metabolism
  • Haploinsufficiency / genetics*
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • Pedigree
  • Sequence Analysis, DNA


  • Codon, Nonsense
  • Contractile Proteins
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • MFAP5 protein, human

Supplementary concepts

  • Aortic Aneurysm, Familial Thoracic 1