Extensive Arterial Tortuosity and Severe Aortic Dilation in a Newborn With an EFEMP2 Mutation

Fibulin-4 E57K Knock-in Mice Recapitulate Cutaneous, Vascular and Skeletal Defects of Recessive Cutis Laxa 1B with both Elastic Fiber and Collagen Fibril Abnormalities

“…Here, we generated and characterized a novel knock-in mouse model corresponding to fibulin-4 E57K homozygous missense mutation found in two unrelated ARCL 1B patients (18,22). Both patients have cutis laxa, ascending aortic aneurysm, vascular tortuosity, and pulmonary emphysema/pneumothorax.…”

“…However, the functional consequences of the missense mutations in vivo remain unclear. To better understand the pathophysiological mechanisms underlying FBLN4 missense mutations in vivo and to develop effective treatments for this life-threatening disorder, we generated a knock-in mouse strain carrying a recurrent homozygous missense mutation found in ARCL 1B patients, the E57K substitution (18,22). We show that the knock-in mice survive into adulthood and display cutaneous, vascular, pulmonary, and skeletal defects reminiscent of the patients with the same missense change.…”

Functional consequence of fibulin-4 missense mutations associated with vascular and skeletal abnormalities and cutis laxa

“…Recently, a number of mutations in the human fibulin-4 gene have been identified in patients affected with vascular abnormalities including aneurysm, arterial tortuosity, cardiovascular diseases, cutis laxa, arachnodactyly, enhanced bone fragility and joint laxity [10][11][12][13][14][15][16][17][18]. Some mutations such as E126K [13,17] or D203A [18] theoretically affect Ca 2 + binding of cbEGF-like modules (Fig.…”

“…Analysis of the molecular consequences of fibulin-4 mutations should provide insight not only into the specific role of distinct amino acids and structural modules in controlling the different functions of fibulin-4, but also help us to understand how the various mutations translate into distinct, but partially overlapping clinical phenotypes. Therefore, in this study we analyzed at molecular level the consequences of missense mutations using recombinantly expressed fibulin-4 mutant proteins bearing single amino acid substitutions E57K [10,16], E126K [13,17], C267Y [12], R297C [11], and A397T [13], and P47S (The substitution of proline 47 by serine was identified as a polymorphism, Dr. Loeys, personal communication); it was therefore used here as control mutant. We compared their synthesis and secretion rates, their proteolytic stability, and their ability to assemble into extracellular fibers, as well as their interaction with extracellular matrix components and enzymes involved in cross-link formation and factors of the TGFβ/LTBP pathway with respect to wild type fibulin-4.…”

Severe Phenotype of Cutis Laxa Type 1B with Antenatal Signs due to a Novel Homozygous Nonsense Mutation in EFEMP2

“…The EFEMP2 protein seems to play an important role in arterial elastic fibers assembly and maturation of smooth muscle cells in the aortic wall [Huang et al, 2009]. In the literature, 46 patients are described with EFEMP2-related cutis laxa [Hucthagowder et al, 2006;Dasouki et al, 2007;Hoyer et al, 2009;Renard et al, 2010;Erickson et al, 2012;Iascone et al, 2012;Kappanayil et al, 2012;Sawyer et al, 2013;Hebson et al, 2014;Rajeshkannan et al, 2014], and 9 Arabic patients only present with arterial manifestations; cutis laxa was not found [Al-Hassnan et al, 2012]. Severity of the disease ranges from perinatal death to manifestations compatible with survival.…”