Association Between Progranulin and Gaucher Disease

Abstract

BackgroundGaucher 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.MethodsSerum 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.FindingsSerum PGRN levels were significantly lower in GD patients (96.65 ± 53.45 ng/ml) than those in healthy controls of the general population (164.99 ± 43.16 ng/ml, p < 0.0001) and of Ashkenazi Jews (150.64 ± 33.99 ng/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.InterpretationOur 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.

Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease

“…1b). In accordance with our previous report that β-GlcCer is accumulated in the lung tissue of PGRN KO mice, lipid composition analysis revealed that GlcCer (Jian et al, 2016), as well as levels of GlcSph (glucosylsphingosine), were significantly higher in both lung and plasma of PGRN KO mice as compared to WT mice (Fig. S2).…”

“…WT and PGRN KO mice after OVA treatment were anesthetized and the lung was processed for TEM or immunogold EM staining at microscope core facility at New York University School of Medicine (Jian et al, 2016). Briefly, mice were euthanized and the lung was perfused with fixative containing 2.5% Glutaraldehyde and 2% paraformaldehyde in 0.1 M sodium cacodylate buffer (pH 7.2) for 2 h. The samples were post fixed in 1% OsO4 for 1 h, block stained with 1% uranyl acetate, dehydrated and embedded in Embed 812 (Electron Microscopy Sciences, Hatfield, PA).…”

“…We recently reported that the four single nucleotide polymorphism (SNP) sites in GRN , the gene encoding PGRN, lead to PGRN insufficiency and have significantly higher frequency in GD patients; revealing an association between PGRN insufficiency and GD (Jian et al, 2016). In addition, “aged” and challenged adult PGRN null mice develop GD-like phenotypes (Jian et al, 2016).…”

“…In addition, “aged” and challenged adult PGRN null mice develop GD-like phenotypes (Jian et al, 2016). However, the mechanisms underlying the association between PGRN and GD remain unclear.…”

Progranulin as a Novel Factor in Gaucher Disease

“…GD may also result from deficient saposin C (Tamaro et al, 2012) or LIMP2 (Reczek et al, 2007), the former is an activator protein of GCase (Tamaro et al, 2012) and the latter is the receptor protein for targeting GCase to the lysosome (Reczek et al, 2007). In a previous study (Jian et al, 2016), these investigators reported that serum PGRN level in GD patients is significantly lower than that in healthy controls, and four SNPs in the GRN gene that encodes PGRN may contribute to this low level. In the present study, they noted that when PGRN KO (knock-out) mice and wild type (WT) mice were challenged using ovalbumin injections and nasal sprays to induce lung inflammation, the PGRN KO mice developed a Gaucher-like phenotype.…”