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Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease

Yildiz, Yildiz ; Hoffmann, Per ; vom Dahl, Stefan ; Breiden, Bernadette ; Sandhoff, Roger ; Niederau, Claus ; Horwitz, Mia ; Karlsson, Stefan LU orcid ; Filocamo, Mirella and Elstein, Deborah , et al. (2013) In Orphanet Journal of Rare Diseases 8.
Abstract
Background: Gaucher disease (GD) is the most common inherited lysosomal storage disorder in humans, caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). GD is clinically heterogeneous and although the type of GBA1 mutation plays a role in determining the type of GD, it does not explain the clinical variability seen among patients. Cumulative evidence from recent studies suggests that GBA2 could play a role in the pathogenesis of GD and potentially interacts with GBA1. Methods: We used a framework of functional and genetic approaches in order to further characterize a potential role of GBA2 in GD. Glucosylceramide (GlcCer) levels in spleen, liver and brain of GBA2-deficient mice and mRNA and protein... (More)
Background: Gaucher disease (GD) is the most common inherited lysosomal storage disorder in humans, caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). GD is clinically heterogeneous and although the type of GBA1 mutation plays a role in determining the type of GD, it does not explain the clinical variability seen among patients. Cumulative evidence from recent studies suggests that GBA2 could play a role in the pathogenesis of GD and potentially interacts with GBA1. Methods: We used a framework of functional and genetic approaches in order to further characterize a potential role of GBA2 in GD. Glucosylceramide (GlcCer) levels in spleen, liver and brain of GBA2-deficient mice and mRNA and protein expression of GBA2 in GBA1-deficient murine fibroblasts were analyzed. Furthermore we crossed GBA2-deficient mice with conditional Gba1 knockout mice in order to quantify the interaction between GBA1 and GBA2. Finally, a genetic approach was used to test whether genetic variation in GBA2 is associated with GD and/or acts as a modifier in Gaucher patients. We tested 22 SNPs in the GBA2 and GBA1 genes in 98 type 1 and 60 type 2/3 Gaucher patients for single-and multi-marker association with GD. Results: We found a significant accumulation of GlcCer compared to wild-type controls in all three organs studied. In addition, a significant increase of Gba2-protein and Gba2-mRNA levels in GBA1-deficient murine fibroblasts was observed. GlcCer levels in the spleen from Gba1/Gba2 knockout mice were much higher than the sum of the single knockouts, indicating a cross-talk between the two glucosylceramidases and suggesting a partially compensation of the loss of one enzyme by the other. In the genetic approach, no significant association with severity of GD was found for SNPs at the GBA2 locus. However, in the multi-marker analyses a significant result was detected for p.L444P (GBA1) and rs4878628 (GBA2), using a model that does not take marginal effects into account. Conclusions: All together our observations make GBA2 a likely candidate to be involved in GD etiology. Furthermore, they point to GBA2 as a plausible modifier for GBA1 in patients with GD. (Less)
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publishing date
type
Contribution to journal
publication status
published
subject
in
Orphanet Journal of Rare Diseases
volume
8
article number
151
publisher
BioMed Central (BMC)
external identifiers
  • wos:000325336300001
  • scopus:84884538436
ISSN
1750-1172
DOI
10.1186/1750-1172-8-151
language
English
LU publication?
yes
id
4a5e28c5-b5c8-4e1f-a9d2-8bf8293b305c (old id 4172161)
date added to LUP
2016-04-01 14:59:58
date last changed
2022-01-28 03:32:10
@article{4a5e28c5-b5c8-4e1f-a9d2-8bf8293b305c,
  abstract     = {{Background: Gaucher disease (GD) is the most common inherited lysosomal storage disorder in humans, caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). GD is clinically heterogeneous and although the type of GBA1 mutation plays a role in determining the type of GD, it does not explain the clinical variability seen among patients. Cumulative evidence from recent studies suggests that GBA2 could play a role in the pathogenesis of GD and potentially interacts with GBA1. Methods: We used a framework of functional and genetic approaches in order to further characterize a potential role of GBA2 in GD. Glucosylceramide (GlcCer) levels in spleen, liver and brain of GBA2-deficient mice and mRNA and protein expression of GBA2 in GBA1-deficient murine fibroblasts were analyzed. Furthermore we crossed GBA2-deficient mice with conditional Gba1 knockout mice in order to quantify the interaction between GBA1 and GBA2. Finally, a genetic approach was used to test whether genetic variation in GBA2 is associated with GD and/or acts as a modifier in Gaucher patients. We tested 22 SNPs in the GBA2 and GBA1 genes in 98 type 1 and 60 type 2/3 Gaucher patients for single-and multi-marker association with GD. Results: We found a significant accumulation of GlcCer compared to wild-type controls in all three organs studied. In addition, a significant increase of Gba2-protein and Gba2-mRNA levels in GBA1-deficient murine fibroblasts was observed. GlcCer levels in the spleen from Gba1/Gba2 knockout mice were much higher than the sum of the single knockouts, indicating a cross-talk between the two glucosylceramidases and suggesting a partially compensation of the loss of one enzyme by the other. In the genetic approach, no significant association with severity of GD was found for SNPs at the GBA2 locus. However, in the multi-marker analyses a significant result was detected for p.L444P (GBA1) and rs4878628 (GBA2), using a model that does not take marginal effects into account. Conclusions: All together our observations make GBA2 a likely candidate to be involved in GD etiology. Furthermore, they point to GBA2 as a plausible modifier for GBA1 in patients with GD.}},
  author       = {{Yildiz, Yildiz and Hoffmann, Per and vom Dahl, Stefan and Breiden, Bernadette and Sandhoff, Roger and Niederau, Claus and Horwitz, Mia and Karlsson, Stefan and Filocamo, Mirella and Elstein, Deborah and Beck, Michael and Sandhoff, Konrad and Mengel, Eugen and Gonzalez, Maria C. and Noethen, Markus M. and Sidransky, Ellen and Zimran, Ari and Mattheisen, Manuel}},
  issn         = {{1750-1172}},
  language     = {{eng}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Orphanet Journal of Rare Diseases}},
  title        = {{Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease}},
  url          = {{https://lup.lub.lu.se/search/files/4292118/4431956.pdf}},
  doi          = {{10.1186/1750-1172-8-151}},
  volume       = {{8}},
  year         = {{2013}},
}