The primary suspicion of vascular EDS with the unsatisfactory identification of a COL3A1 benign variant was secondarily readjusted with the identification of COL1A1 p.(Arg312Cys) variant.
We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance.
A sequencing analysis of the COL3A1 gene identified a novel, de novo missense mutation that confirmed the diagnosis of vascular Ehlers-Danlos syndrome (EDS).
Although vascular Ehlers-Danlos syndrome appears to be genetically homogeneous, allelic heterogeneity is marked, and the natural history varies with gender and type of mutation in COL3A1.
Based on the previous finding that mutations in COL3A1 cause type IV EDS, our study indicates a possible common pathological pathway linking connective tissue diseases and brain malformations.
Aortic dilatation/dissection (AD) can occur spontaneously or in association with genetic syndromes, such as Marfan syndrome (MFS; caused by FBN1 mutations), MFS type 2 and Loeys-Dietz syndrome (associated with TGFBR1/TGFBR2 mutations), and Ehlers-Danlos syndrome (EDS) vascular type (caused by COL3A1 mutations).
Dermal fibroblasts derived from types I and IV Ehlers-Danlos syndrome (EDS) patients, carrying mutations in COL5A1 and COL3A1 genes, respectively, synthesize aberrant types V and III collagen (COLL) and show defective organization of these proteins into the extracellular matrix (ECM) and high reduction of their functional receptor, the alpha(2)beta(1) integrin, compared with control fibroblasts.
Vascular Ehlers Danlos syndrome (EDS) is a rare autosomal dominant inherited disorder of connective tissue resulting from mutation of the COL3A1 gene encoding type III collagen.
The sequence of the COL3A1 gene from the patients with EDS type IV-like alterations of the connective tissue morphology was analyzed.No mutation was detected.
Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those of the vascular form of EDS.
Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those of the vascular form of EDS.
A large kindred with EDS type IV was studied clinically, and the biochemical defects and underlying mutation in the COL3A1 gene that encodes the chains of type III procollagen were identified.
Ehlers-Danlos syndrome (EDS) type IV is a heritable disorder resulting from mutations in the COL3A1 gene that cause deficient production of type III collagen.
This mutation is analogous to mutations causing exon skipping in the major collagen genes, COL1A1, COL1A2, and COL3A1, identified in several cases of osteogenesis imperfecta and EDS type IV.