Miolo Gianmaria, Machin Piernicola, De Conto Marco, Fortuna Sara, Viglio Simona, Della Puppa Lara, Geremia Silvano, Corona Giuseppe
Medical Oncology and Cancer Prevention Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
Pathology Unit, Department of Medicine Laboratory Section, Pordenone Hospital, Pordenone, Italy.
Mol Genet Genomic Med. 2025 Apr;13(4):e70095. doi: 10.1002/mgg3.70095.
Vascular Ehlers-Danlos syndrome (vEDS) is caused by alterations in the COL3A1 gene, typically involving missense variants that replace glycine residues. In contrast, short in-frame insertions, deletions, and duplications are rare and pose significant challenges for investigation.
The histological examination of vascular tissue from a 26-year-old man, who died from a common iliac artery aneurysm and whose mother died at age 60 from an abdominal aortic dissection, strongly suggested a diagnosis of Ehler-Danlos type IV. Ex vivo collagen phenotype assessment, molecular analysis, and in silico structural studies of type III collagen were subsequently performed.
Ex vivo analysis of the patient's fibroblasts revealed altered collagen synthesis, whereas the molecular testing identified a novel 18-nucleotide in-frame duplication (c.2868_2885dup-GGGTCTTGCAGGACCACC) in the COL3A1 gene, resulting in a six-amino acid insertion, p.(Leu958_Gly963dup). Structural investigation indicated that this duplication led to a local perturbation of the collagen triple helix near a metalloproteinase cleavage site.
This study highlights the pathogenic role of a novel in-frame duplication in the COL3A1 gene, demonstrating how this seemingly benign alteration significantly compromises collagen turnover and contributes to the development of vEDS.
血管型埃勒斯-当洛综合征（vEDS）由COL3A1基因改变引起，通常涉及取代甘氨酸残基的错义变异。相比之下，框内短插入、缺失和重复很少见，给研究带来重大挑战。
对一名26岁男性的血管组织进行组织学检查，该男性死于髂总动脉瘤，其母亲60岁时死于腹主动脉夹层，强烈提示诊断为IV型埃勒斯-当洛综合征。随后对III型胶原蛋白进行了体外胶原蛋白表型评估、分子分析和计算机结构研究。
对患者成纤维细胞的体外分析显示胶原蛋白合成改变，而分子检测在COL3A1基因中发现了一个新的18核苷酸框内重复（c.2868_2885dup-GGGTCTTGCAGGACCACC），导致六个氨基酸插入，即p.(Leu958_Gly963dup)。结构研究表明，这种重复导致金属蛋白酶切割位点附近的胶原蛋白三螺旋局部扰动。
本研究强调了COL3A1基因中一种新的框内重复的致病作用，证明了这种看似良性的改变如何显著损害胶原蛋白周转并导致vEDS的发生。
