| Autor: |
Pavan E; Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy., Peruzzo P; Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy., Cattarossi S; Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy., Bergamin N; Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy., Bordugo A; Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy., Sechi A; Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy., Scarpa M; Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy., Biasizzo J; Clinical Pathology Division, Department of Laboratory Medicine, University Hospital Friuli Centrale ASUFC, 33100 Udine, Italy., Colucci F; Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy., Dardis A; Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy. |
| Abstrakt: |
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. |
