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Author information:
Malekkou A1,2, Samarani M3, Drousiotou A4,5, Votsi C6,7, Sonnino S8, Pantzaris M9,10, Chiricozzi E11, Zamba-Papanicolaou E12,13, Aureli M14, Loberto N15, Christodoulou K16,17.
Author information
1 Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus. annama@cing.ac.cy.
2 Cyprus School of Molecular Medicine, Nicosia 1683, Cyprus. annama@cing.ac.cy.
3 Department of Medical Biotechnology and Translational Medicine, University of Milano, 20122 Milano, Italy. maura.samarani@unimi.it.
4 Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus. anthidr@cing.ac.cy.
5 Cyprus School of Molecular Medicine, Nicosia 1683, Cyprus. anthidr@cing.ac.cy.
6 Cyprus School of Molecular Medicine, Nicosia 1683, Cyprus. votsi@cing.ac.cy.
7 Neurogenetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus. votsi@cing.ac.cy.
8 Department of Medical Biotechnology and Translational Medicine, University of Milano, 20122 Milano, Italy. sandro.sonnino@unimi.it.
9 Cyprus School of Molecular Medicine, Nicosia 1683, Cyprus. pantzari@cing.ac.cy.
10 Neurology Clinic C, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus. pantzari@cing.ac.cy.
11 Department of Medical Biotechnology and Translational Medicine, University of Milano, 20122 Milano, Italy. elena.chiricozzi@unimi.it.
12 Cyprus School of Molecular Medicine, Nicosia 1683, Cyprus. ezamba@cing.ac.cy.
13 Neurology Clinic D, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus. ezamba@cing.ac.cy.
14 Department of Medical Biotechnology and Translational Medicine, University of Milano, 20122 Milano, Italy. massimo.aureli@unimi.it.
15 Department of Medical Biotechnology and Translational Medicine, University of Milano, 20122 Milano, Italy. nicoletta.loberto@unimi.it.
16 Cyprus School of Molecular Medicine, Nicosia 1683, Cyprus. roula@cing.ac.cy.
17 Neurogenetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus. roula@cing.ac.cy.

Abstract
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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