胶原IV型α1和α2(COL4A1和COL4A2)是几乎所有基底膜的主要成分。COL4A1和COL4A2突变引起多系统疾病,可以影响任何器官,但通常涉及脑血管系统,眼睛,肾脏和骨骼肌.近年来,患者倡导和家庭支持团体以古尔德综合症的名义联合起来。古尔德综合征的表现变化很大,和动物研究表明,等位基因异质性和遗传背景有助于临床变异性。我们先前描述了由Col4a1突变引起的Gould综合征的小鼠模型,其中眼眼前节发育不全(ASD)的严重性,肌病和脑出血(ICH)取决于遗传背景。这里,我们进行了遗传修饰筛选,以深入了解Gould综合征发病机制,并在1号染色体上确定了抑制ASD的单个基因座[Gould综合征1(MoGS1)的修饰]。单独的屏幕显示相同的基因座改善了肌病。有趣的是,MoGS1对ICH没有影响,表明这种表型可能是机械上不同的。我们将MoGS1基因座细化为包含18个蛋白质编码基因的4.3Mb间隔,包括编码细胞外基质成分纤连蛋白1的Fn1。分子分析显示MoGS1位点增加Fn1表达,提高了通过补偿性细胞外机制实现抑制的可能性。此外,我们发现Col4a1突变小鼠中整合素连接激酶水平和粘着斑激酶磷酸化增加的证据,通过MoGS1基因座部分恢复,涉及整合素信号的参与。一起来看,我们的结果表明,组织特异性机制异质性有助于Gould综合征的可变表达,整合素信号的扰动可能在眼部和肌肉表现中起作用.
Collagen type IV alpha 1 and alpha 2 (COL4A1 and COL4A2) are major components of almost all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that can affect any organ but typically involves the cerebral vasculature, eyes, kidneys and skeletal muscles. In recent years, patient advocacy and family support groups have united under the name of Gould syndrome. The manifestations of Gould syndrome are highly variable, and animal studies suggest that allelic heterogeneity and genetic context contribute to the clinical variability. We previously characterized a mouse model of Gould syndrome caused by a Col4a1 mutation in which the severities of ocular anterior segment dysgenesis (ASD), myopathy and intracerebral hemorrhage (ICH) were dependent on genetic background. Here, we performed a genetic modifier screen to provide insight into the mechanisms contributing to Gould syndrome pathogenesis and identified a single locus [modifier of Gould syndrome 1 (MoGS1)] on Chromosome 1 that suppressed ASD. A separate screen showed that the same locus ameliorated myopathy. Interestingly, MoGS1 had no effect on ICH, suggesting that this phenotype could be mechanistically distinct. We refined the MoGS1 locus to a 4.3 Mb interval containing 18 protein-coding genes, including Fn1, which encodes the extracellular matrix component fibronectin 1. Molecular analysis showed that the MoGS1 locus increased Fn1 expression, raising the possibility that suppression is achieved through a compensatory extracellular mechanism. Furthermore, we found evidence of increased integrin-linked kinase levels and focal adhesion kinase phosphorylation in Col4a1 mutant mice that is partially restored by the MoGS1 locus, implicating the involvement of integrin signaling. Taken together, our results suggest that tissue-specific mechanistic heterogeneity contributes to the variable expressivity of Gould syndrome and that perturbations in integrin signaling may play a role in ocular and muscular manifestations.