Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of ß-glucocerebrosidase (GCase). This study identified the progranulin (PGRN) gene (GRN) as another gene associated with GD.Serum levels of PGRN were measured from 115 GD patients and 99 healthy controls, whole GRN gene from 40 GD patients was sequenced, and the genotyping of 4 SNPs identified in GD patients was performed in 161 GD and 142 healthy control samples. Development of GD in PGRN-deficient mice was characterized, and the therapeutic effect of rPGRN on GD analyzed.Serum PGRN levels were significantly lower in GD patients (96.65±53.45ng/ml) than those in healthy controls of the general population (164.99±43.16ng/ml, p<0.0001) and of ashkenazi jews (150.64±33.99ng/ml, p<0.0001). four grn gene snps, including rs4792937, rs78403836, rs850713, rs5848, three point mutations, were identified in a full-length sequencing 40 gd patients. large scale snp genotyping 161 142 healthy controls was conducted the sites have significantly higher frequency addition, "aged" challenged adult pgrn null mice develop gd-like phenotypes, typical gaucher-like cells lung, spleen, bone marrow. moreover, lysosomes ko exhibit tubular-like appearance. is required for lysosomal appearance gcase its deficiency leads to accumulation cytoplasm. more importantly, recombinant therapeutic various animal models human fibroblasts from patients.our data demonstrates an unknown association between identifies as essential factor gcase's localization. these findings not only provide new insight into pathogenesis gd, but may also implications diagnosis alternative targeted therapies gd. copyright © 2016 forschungsgesellschaft für arbeitsphysiologie und arbeitschutz e.v. published by elsevier b.v. all rights reserved.
Journal: EBioMedicine
DOI: 10.1016/j.ebiom.2016.08.004
Year: 2016