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Orphanet J Rare Dis. 2024 Jan 5;19(1):9. doi: 10.1186/s13023-023-03007-7.
Ehlers-Danlos syndrome Type IV (aka Vascular Ehlers Danlos, or vEDS) is a dominantly inherited mutation in the Collagen 3A1 gene (COL3A1). The disease is characterized by tissue friability and age-related susceptibility to arterial aneurysm, dissection and rupture as well as uterine and bowl tears. These clinical manifestations result in major surgical intervention and decreased life expectancy. Understanding how mutations in COL3A1 impact the structure and function of the extracellular matrix (ECM) is important to managing the disease and finding treatments.
Skin fibroblasts from vEDS subjects heterozygous for the p.G588S pathogenic variant in the COL3A1 gene and a normal individual were cultured and studied. Proteomics analysis identified dozens of upregulated proteins related to extracellular matrix dysregulation that is characteristic of fibrosis. Gene expression libraries from cultured primary fibroblasts were screened for messenger RNA (mRNA) markers of ECM degradation. The proteomics and targeted gene expression array results were largely consistent with dysregulation of the extracellular matrix in vEDS. The data show upregulation of multiple Collagen proteins and genes, other ECM components, and enzymes related to ECM processing and turn-over. vEDS fibroblasts expressed significantly more cross linked C-Telopeptide of Collagen III (CTXIII) than normal fibroblasts, indicative of Collagen III degradation and turn-over. Further, the expression and activity of Lysyl Oxidase (LOX), an enzyme that initiates covalent cross-linking of soluble collagen and elastin into protease resistant fibers, is elevated in vEDS fibroblasts compared to normal fibroblasts.
Together, these findings suggest dysregulated ECM deposition and processing, reminiscent of a state of fibrosis. Therapeutics that target the dysregulated ECM proteins or help replace damaged tissue may improve clinical outcomes.
Ehlers-Danlos 综合征 IV 型（又称血管型 Ehlers-Danlos，或 vEDS）是胶原 3A1 基因（COL3A1）的显性遗传突变。该疾病的特征是组织脆弱，以及与年龄相关的易发性动脉瘤、夹层和破裂，以及子宫和肠道撕裂。这些临床表现导致主要的手术干预和预期寿命缩短。了解 COL3A1 突变如何影响细胞外基质（ECM）的结构和功能对于管理疾病和寻找治疗方法非常重要。
培养并研究了 COL3A1 基因中 p.G588S 致病变异杂合的 vEDS 受试者和正常个体的皮肤成纤维细胞。蛋白质组学分析鉴定了数十种与纤维化特征的细胞外基质失调相关的上调蛋白。对培养的原代成纤维细胞的基因表达文库进行了细胞外基质降解的信使 RNA（mRNA）标志物的筛选。蛋白质组学和靶向基因表达阵列结果与 vEDS 中的细胞外基质失调基本一致。数据显示多种胶原蛋白蛋白和基因、其他细胞外基质成分以及与细胞外基质加工和周转相关的酶的上调。vEDS 成纤维细胞表达的交联型 III 型胶原 C-端肽（CTXIII）明显多于正常成纤维细胞，表明 III 型胶原的降解和周转。此外，与正常成纤维细胞相比，赖氨酰氧化酶（LOX）的表达和活性升高，LOX 是一种将可溶性胶原蛋白和弹性蛋白共价交联成蛋白酶抗性纤维的酶。
综上所述，这些发现表明细胞外基质沉积和加工失调，类似于纤维化状态。针对失调的细胞外基质蛋白的治疗方法或有助于替代受损组织的治疗方法可能改善临床结果。
