Stembridge Natasha S, Vandersteen Anthony M, Ghali Neeti, Sawle Philip, Nesbitt Mandy, Pollitt Rebecca C, Ferguson David J P, Holden Simon, Elmslie Frances, Henderson Alex, Hulmes David J S, Pope F Michael
Ehlers-Danlos Syndrome, National Diagnostic Service Northwick Park and St. Mark's Hospitals, Harrow, UK.
Maritime Medical Genetics Service, IWKHealth Centre, Halifax, Nova Scotia, Canada.
Am J Med Genet A. 2015 Aug;167A(8):1763-72. doi: 10.1002/ajmg.a.37081. Epub 2015 Apr 5.
Vascular Ehlers-Danlos syndrome (vEDS) is a heritable disorder of connective tissue caused by pathological variants in the COL3A1 gene, which encodes the α1 chain of type III collagen. Type III collagen is a major component of skin, arterial walls, and the gastrointestinal tract. Collagen III protein deficiency manifests as an increased risk of rupture, perforation, and dissection of these structures. The most disruptive gene variants affect the collagen helix via glycine substitutions or splice donor site mutations. The C-propeptide region of COL3A1 includes exons 49-52 and has a crucial role in initiating the C-terminal assembly of procollagen monomers in the early stages of collagen biosynthesis. Nineteen COL3A1 variants have previously been reported in these exons, of which four were associated with a severe vEDS phenotype. We identified two novel C-propeptide missense variants; p.Pro1440Leu, p.Arg1432Leu, and a non-stop mutation, c.4400A > T, p. (1467Leuext45). These variants produce variable phenotypes ranging from obvious acrogeria to classical or hypermobile EDS. A previously reported variant p.Lys1313Arg is of unknown clinical significance but likely benign, based on this study. Assigning disease pathogenicity remains complex, clinical phenotyping and crystal structure evidence being crucial. We briefly compare reported phenotypes for patients with missense variants in the C-propeptide domain for other human collagen disorders including COL1A1 and COL1A2 (osteogenesis imperfecta).
血管型埃勒斯-当洛综合征（vEDS）是一种由COL3A1基因突变引起的遗传性结缔组织疾病，该基因编码III型胶原蛋白的α1链。III型胶原蛋白是皮肤、动脉壁和胃肠道的主要成分。胶原蛋白III蛋白缺乏表现为这些结构破裂、穿孔和夹层形成的风险增加。最具破坏性的基因突变通过甘氨酸替代或剪接供体位点突变影响胶原蛋白螺旋。COL3A1的C-前肽区域包括外显子49-52，在胶原蛋白生物合成早期启动原胶原蛋白单体的C端组装中起关键作用。此前已在这些外显子中报道了19种COL3A1变体，其中4种与严重的vEDS表型相关。我们鉴定出两种新的C-前肽错义变体：p.Pro1440Leu、p.Arg1432Leu，以及一种无义突变，c.4400A > T，p.（1467Leuext45）。这些变体产生的表型各不相同，从明显的肢端早老症到经典型或活动过度型EDS。根据本研究，先前报道的变体p.Lys1313Arg临床意义未知，但可能为良性。确定疾病致病性仍然很复杂，临床表型分析和晶体结构证据至关重要。我们简要比较了其他人类胶原蛋白疾病（包括COL1A1和COL1A2，成骨不全）中C-前肽结构域错义变体患者的报告表型。
