PDF(Pubmed)
Abstract：
Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the proteolytical cleavage of prosaposin (encoded by PSAP gene), which gives rise to four saposins. GCase is targeted to the lysosomes by LIMP-2, encoded by SCARB2 gene. GCase deficiency causes Gaucher Disease (GD), which is mainly due to biallelic pathogenetic variants in the GCase-encoding gene, GBA1. However, impairment of GCase activity can be rarely caused by SapC or LIMP-2 deficiencies. We report a new case of LIMP-2 deficiency and a new case of SapC deficiency (missing all four saposins, PSAP deficiency), and measured common biomarkers of GD and GCase activity. Glucosylsphingosine and chitotriosidase activity in plasma were increased in GCase deficiencies caused by PSAP and GBA1 mutations, whereas SCARB2-linked deficiency showed only Glucosylsphingosine elevation. GCase activity was reduced in fibroblasts and leukocytes: the decrease was sharper in GBA1- and SCARB2-mutant fibroblasts than PSAP-mutant ones; LIMP-2-deficient leukocytes displayed higher residual GCase activity than GBA1-mutant ones. Finally, we demonstrated that GCase mainly undergoes proteasomal degradation in LIMP-2-deficient fibroblasts and lysosomal degradation in PSAP-deficient fibroblasts. Thus, we analyzed the differential biochemical profile of GCase deficiencies due to the ultra-rare PSAP and SCARB2 biallelic pathogenic variants in comparison with the profile observed in GBA1-linked GCase deficiency.
摘要：
葡糖脑苷脂酶（GCase）是一种溶酶体酶，在其激活剂saposinC（SapC）存在下催化葡萄糖神经酰胺的分解。SapC来自prosaposin（由PSAP基因编码）的蛋白水解裂解，这就产生了四个saposins。GCase通过SCARB2基因编码的LIMP-2靶向溶酶体。GCase缺乏导致戈谢病（GD），这主要是由于GCase编码基因的双等位基因致病变异，GBA1。然而,GCase活性的损害很少是由SapC或LIMP-2缺陷引起的。我们报告了一例新的LIMP-2缺乏症和一例新的SapC缺乏症（缺少所有四种Saposin，PSAP不足)，并测量了GD和GCase活性的常见生物标志物。在PSAP和GBA1突变引起的GCase缺陷中，血浆中的葡糖鞘氨醇和壳三糖苷酶活性增加，而SCARB2相关缺陷仅显示葡萄糖鞘氨醇升高。成纤维细胞和白细胞中的GCase活性降低：GBA1-和SCARB2突变型成纤维细胞的降低比PSAP突变型成纤维细胞的降低更明显；LIMP-2缺陷型白细胞显示出比GBA1突变型更高的残余GCase活性。最后,我们证明GCase主要在LIMP-2缺陷的成纤维细胞中经历蛋白酶体降解,在PSAP缺陷的成纤维细胞中经历溶酶体降解.因此，我们分析了由于超罕见PSAP和SCARB2双等位基因致病变异导致的GCase缺陷的差异生化特征,并与GBA1相关的GCase缺陷中观察到的特征进行比较.
