Association Between Progranulin and Gaucher Disease

EBioMedicine. 2016 Sep:11:127-137. doi: 10.1016/j.ebiom.2016.08.004. Epub 2016 Aug 4.


Background: Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of β-glucocerebrosidase (GCase). This study identified the progranulin (PGRN) gene (GRN) as another gene associated with GD.

Methods: 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.

Findings: 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, and rs5848, and three point mutations, were identified in a full-length GRN gene sequencing in 40 GD patients. Large scale SNP genotyping in 161 GD and 142 healthy controls was conducted and the four SNP sites have significantly higher frequency in GD patients. In addition, "aged" and challenged adult PGRN null mice develop GD-like phenotypes, including typical Gaucher-like cells in lung, spleen, and bone marrow. Moreover, lysosomes in PGRN KO mice exhibit a tubular-like appearance. PGRN is required for the lysosomal appearance of GCase and its deficiency leads to GCase accumulation in the cytoplasm. More importantly, recombinant PGRN is therapeutic in various animal models of GD and human fibroblasts from GD patients.

Interpretation: Our data demonstrates an unknown association between PGRN and GD and identifies PGRN as an essential factor for GCase's lysosomal localization. These findings not only provide new insight into the pathogenesis of GD, but may also have implications for diagnosis and alternative targeted therapies for GD.

Keywords: Gaucher disease; Lysosomal storage diseases; Progranulin; β-Glucocerebrosidase.

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Animals
  • Case-Control Studies
  • Disease Models, Animal
  • Enzyme Activation
  • Female
  • Gaucher Disease / blood
  • Gaucher Disease / diagnosis
  • Gaucher Disease / genetics*
  • Gene Frequency
  • Genetic Association Studies*
  • Genotype
  • Humans
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Lysosomes / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Mutation
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Progranulins
  • Protein Transport


  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins