GBA2 Mutations Cause a Marinesco-Sjögren-Like Syndrome: Genetic and Biochemical Studies

Haugarvoll, Kristoffer; Johansson, Stefan; Rodríguez, Corina Iris; Boman, Helge; Haukanes, Bjørn Ivar; Bruland, Ove; Roque, Francisco S.; Jonassen, Inge; Blomqvist, Maria; Telstad, Wenche; Månsson, Jan‐Eric; Knappskog, Per M.; Bindoff, Laurence A.

doi:10.1371/journal.pone.0169309

Cited by 20 publications

(24 citation statements)

References 25 publications

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“…Despite the abnormal GlcCer accumulation in brain, GBA2 -knockout mice do not display any neurological symptoms or defects [ 19 ]. On the contrary, GBA2 -knockdown zebrafish show abnormal motor neuron development [ 21 ], and mutations in the human GBA2 gene have been found to lead to neurological disorders like spastic ataxia (SA) [ 22 , 23 ], hereditary spastic paraplegia (HSP) [ 21 , 24 , 25 ], and more recently Marinesco-Sjogren-Like Syndrome [ 26 ]. The molecular mechanism(s) leading to the development of disease are not currently known.…”

Section: Introductionmentioning

confidence: 99%

Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia

Malekkou

Samarani

Drousiotou

et al. 2018

IJMS

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The GBA2 gene encodes the non-lysosomal glucosylceramidase (NLGase), an enzyme that catalyzes the conversion of glucosylceramide (GlcCer) to ceramide and glucose. Mutations in GBA2 have been associated with the development of neurological disorders such as autosomal recessive cerebellar ataxia, hereditary spastic paraplegia, and Marinesco-Sjogren-Like Syndrome. Our group has previously identified the GBA2 c.1780G>C [p.Asp594His] missense mutation, in a Cypriot consanguineous family with spastic ataxia. In this study, we carried out a biochemical characterization of lymphoblastoid cell lines (LCLs) derived from three patients of this family. We found that the mutation strongly reduce NLGase activity both intracellularly and at the plasma membrane level. Additionally, we observed a two-fold increase of GlcCer content in LCLs derived from patients compared to controls, with the C16 lipid being the most abundant GlcCer species. Moreover, we showed that there is an apparent compensatory effect between NLGase and the lysosomal glucosylceramidase (GCase), since we found that the activity of GCase was three-fold higher in LCLs derived from patients compared to controls. We conclude that the c.1780G>C mutation results in NLGase loss of function with abolishment of the enzymatic activity and accumulation of GlcCer accompanied by a compensatory increase in GCase.

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Section: Introductionmentioning

confidence: 99%

Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia

Malekkou

Samarani

Drousiotou

et al. 2018

IJMS

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“…Single nucleotide polymorphism (SNP) is the third generation of molecular marker and one of the most common genetic variations in human. Studies show that SNP can not only be used as a genetic marker locating disease gene, some SNP itself can also directly lead to the occurrence of diseases [ 9 , 10 ]. Thus SNP has crucial function and application in disease risk assessment, early diagnosis, prevention, treatment and drug development [ 11 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Single nucleotide polymorphisms in MLH1 predict poor prognosis of hepatocellular carcinoma in a Chinese population

et al. 2017

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Hepatocellular carcinoma (HCC) is a malignant cancer causing deleterious health effect worldwide, especially in China. So far clinical cure rate and long-term survival rate of HCC remains low. Most HCC patients after cancer resection have recurrence or metastasis within 5 years. This study aims to explore the genetic association of mutL homolog 1 (MLH1) polymorphisms with HCC risk and prognosis. Four candidate MLH1 polymorphisms, rs1800734, rs10849, rs3774343 and rs1540354 were studied from a hospital-based case-control study including 1,036 cases (HCC patients) and 1,036 controls (non-HCC patients) in Guangxi, China. All these SNPs interacted with environmental risk factors, such as HBV infection, alcohol intake and smoking in the pathogenesis of HCC. However, only rs1800734 had significant difference between cases and controls. Compared to the AA genotype, patients with AG, GG and AG/GG genotype of rs1800734 had an increased risk of HCC [ORs (95% CI) = 1.217 (1.074∼1.536), 1.745 (1.301∼2.591) and 1.291 (1.126∼1.687)] and a decreased survival time [co-dominant, HR (95% CI) = 1.553 (1.257∼1.920); dominant, HR (95% CI) = 2.207 (1.572∼3.100)]. Furthermore, we found that tumor number, tumor staging, metastasis and rs1800734 were associated with the overall survival of HCC patients by multivariate COX regression analysis. No significant difference was found between the other three MLH1 polymorphisms with HCC risk and prognosis. Our study suggests MLH1 SNP, rs1800734 as a new predictor for poor prognosis of HCC patients.

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“…GBA2 deficiency is responsible for a heterologous group of ataxias, including hereditary spastic paraplegia, autosomal recessive cerebellar ataxia with spasticity and Marinesco-Sjogren-like syndrome (31)(32)(33) . The molecular basis of how GBA2 deficiency leads to these syndromes and the basis for their heterogeneity are not well understood.…”

Section: Discussionmentioning

confidence: 99%

Effect of expression of human glucosylceramidase 2 isoforms on lipid profiles in COS-7 cells

Jatooratthawichot

Talabnin

Ngiwsara

et al. 2020

Preprint

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AbstractGlucosylceramide (GlcCer) is a major membrane lipid and the precursor of gangliosides. It is continuously formed and degraded in glycosphingolipid metabolism. GlcCer is mainly degraded by two enzymes, lysosomal acid β-glucosidase (GBA) and nonlysosomal β-glucosidase (GBA2). Deficiencies of GBA and GBA2 affect glycosphingolipid metabolism, resulting in neurological diseases, such as Gaucher Disease and Hereditary Spastic Paraplegia. To understand which GBA2 isoforms are active and how they affect glycosphingolipid levels in cells, we expressed nine human GBA2 isoforms in COS-7 cells, confirmed their expression by qRT-PCR and western blotting, and assayed their activity to hydrolyze 4-methylumbelliferyl-β-D-glucopyranoside (4MUG) in cell extracts. Human GBA2 isoform 1 showed high activity, while the other isoforms had activity similar to the background. Comparison of sphingolipid levels by ultra-high resolution/ accurate mass spectrometry (UHRAMS) analysis showed that isoform 1 overexpression increased ceramide and decreased hexosylceramide levels compared to control and other isoforms. Comparison of ratios of glucosylceramides to the corresponding ceramides in the extracts indicated that GBA2 isoform 1 has broad specificity for the lipid component of glucosylceramide. These studies suggest that only one GBA2 isoform 1 is active and affects sphingolipid levels in the cell, acting on glucosylceramides with a wide range of lipid components. Our study provides new insights into how increased breakdown of GlcCer affects cellular lipid metabolic networks.

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GBA2 Mutations Cause a Marinesco-Sjögren-Like Syndrome: Genetic and Biochemical Studies

Cited by 20 publications

References 25 publications

Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia

Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia

Single nucleotide polymorphisms in MLH1 predict poor prognosis of hepatocellular carcinoma in a Chinese population

Effect of expression of human glucosylceramidase 2 isoforms on lipid profiles in COS-7 cells

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