title: Association Between Progranulin and Gaucher Disease.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Jinlong
authors: J
authors: Jian
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Shuai
authors: S
authors: Zhao
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Qing-Yun
authors: QY
authors: Tian
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Helen
authors: H
authors: Liu
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Yunpeng
authors: Y
authors: Zhao
authors: Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States.
authors: Wen-Chi
authors: WC
authors: Chen
authors: Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States.
authors: Gabriele
authors: G
authors: Grunig
authors: Department of Neurology, New York University School of Medicine, 550 First Ave, New York, NY 10016, United States.
authors: Paola A
authors: PA
authors: Torres
authors: Department of Neurology, New York University School of Medicine, 550 First Ave, New York, NY 10016, United States.
authors: Betty C
authors: BC
authors: Wang
authors: Department of Neurology, New York University School of Medicine, 550 First Ave, New York, NY 10016, United States.
authors: Bai
authors: B
authors: Zeng
authors: Department of Neurology, New York University School of Medicine, 550 First Ave, New York, NY 10016, United States.
authors: Gregory
authors: G
authors: Pastores
authors: Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan 250012, People's Republic of China.
authors: Wei
authors: W
authors: Tang
authors: The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
authors: Ying
authors: Y
authors: Sun
authors: The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
authors: Gregory A
authors: GA
authors: Grabowski
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors: Max Xiangtian
authors: MX
authors: Kong
authors: Yale Center for Genome Analysis, Yale university, 830 West Campus Drive, Orange, CT 06477, United States.
authors: Guilin
authors: G
authors: Wang
authors: Depression Evaluation Service, New York, State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, United States.
authors: Ying
authors: Y
authors: Chen
authors: Microscope Core Facility, New York University School of Medicine, New York, NY 10016, United States.
authors: Fengxia
authors: F
authors: Liang
authors: Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA Leiden, Netherlands.
authors: Herman S
authors: HS
authors: Overkleeft
authors: Department of Neurology, Beth Israel Medical Center, New York, NY 10003, United States.
authors: Rachel
authors: R
authors: Saunders-Pullman
authors: Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA 02115, United States.
authors: Gerald L
authors: GL
authors: Chan
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, United States. Electronic address: chuanju.liu@nyumc.org.
authors: Chuan-Ju
authors: CJ
authors: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D005776:Gaucher Disease / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D021381:Protein Transport
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins
keywords: Gaucher disease; Lysosomal storage diseases; Progranulin; β-Glucocerebrosidase