Department of Internal Medicine I, University Clinic of Bonn, Bonn, Germany.
Orphanet J Rare Dis. 2013 Sep 26;8:151. doi: 10.1186/1750-1172-8-151.
Gaucher disease (GD) is the most common inherited lysosomal storage disorder in humans, caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). GD is clinically heterogeneous and although the type of GBA1 mutation plays a role in determining the type of GD, it does not explain the clinical variability seen among patients. Cumulative evidence from recent studies suggests that GBA2 could play a role in the pathogenesis of GD and potentially interacts with GBA1.
We used a framework of functional and genetic approaches in order to further characterize a potential role of GBA2 in GD. Glucosylceramide (GlcCer) levels in spleen, liver and brain of GBA2-deficient mice and mRNA and protein expression of GBA2 in GBA1-deficient murine fibroblasts were analyzed. Furthermore we crossed GBA2-deficient mice with conditional Gba1 knockout mice in order to quantify the interaction between GBA1 and GBA2. Finally, a genetic approach was used to test whether genetic variation in GBA2 is associated with GD and/ or acts as a modifier in Gaucher patients. We tested 22 SNPs in the GBA2 and GBA1 genes in 98 type 1 and 60 type 2/3 Gaucher patients for single- and multi-marker association with GD.
We found a significant accumulation of GlcCer compared to wild-type controls in all three organs studied. In addition, a significant increase of Gba2-protein and Gba2-mRNA levels in GBA1-deficient murine fibroblasts was observed. GlcCer levels in the spleen from Gba1/Gba2 knockout mice were much higher than the sum of the single knockouts, indicating a cross-talk between the two glucosylceramidases and suggesting a partially compensation of the loss of one enzyme by the other. In the genetic approach, no significant association with severity of GD was found for SNPs at the GBA2 locus. However, in the multi-marker analyses a significant result was detected for p.L444P (GBA1) and rs4878628 (GBA2), using a model that does not take marginal effects into account.
All together our observations make GBA2 a likely candidate to be involved in GD etiology. Furthermore, they point to GBA2 as a plausible modifier for GBA1 in patients with GD.
戈谢病（GD）是人类最常见的遗传性溶酶体贮积症，由溶酶体酶葡萄糖脑苷脂酶（GBA1）编码基因的突变引起。GD 临床表现具有异质性，尽管 GBA1 突变类型在确定 GD 类型方面起作用，但它并不能解释患者之间存在的临床变异性。最近的研究累积证据表明，GBA2 可能在 GD 的发病机制中起作用，并可能与 GBA1 相互作用。
我们使用功能和遗传方法框架，以进一步表征 GBA2 在 GD 中的潜在作用。分析 GBA2 缺陷小鼠的脾、肝和脑中的葡萄糖脑苷脂（GlcCer）水平以及 GBA1 缺陷鼠成纤维细胞中的 GBA2mRNA 和蛋白表达。此外，我们将 GBA2 缺陷小鼠与条件性 Gba1 敲除小鼠杂交，以定量 GBA1 和 GBA2 之间的相互作用。最后，采用遗传方法检测 GBA2 中的遗传变异是否与 GD 相关，以及/或是否在 Gaucher 患者中作为修饰因子。我们在 98 名 1 型和 60 名 2/3 型 Gaucher 患者中测试了 GBA2 和 GBA1 基因中的 22 个 SNP，以进行单标记和多标记与 GD 的关联分析。
与野生型对照相比，我们发现所有三种研究器官中的 GlcCer 显著积累。此外，在 GBA1 缺陷鼠成纤维细胞中观察到 Gba2-蛋白和 Gba2-mRNA 水平显著增加。Gba1/Gba2 敲除小鼠脾脏中的 GlcCer 水平远高于单个敲除小鼠的总和，表明两种葡萄糖脑苷脂酶之间存在交叉对话，并表明一种酶的缺失由另一种酶部分补偿。在遗传方法中，在 GBA2 基因座上未发现 SNP 与 GD 严重程度显著相关。然而，在不考虑边缘效应的模型中，多标记分析检测到 p.L444P（GBA1）和 rs4878628（GBA2）的显著结果。
总的来说，我们的观察结果使 GBA2 成为参与 GD 病因的一个可能候选者。此外，它们表明 GBA2 是 GD 患者中 GBA1 的一个合理修饰因子。
