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Article

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

1
Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus
2
Cyprus School of Molecular Medicine, Nicosia 1683, Cyprus
3
Department of Medical Biotechnology and Translational Medicine, University of Milano, 20122 Milano, Italy
4
Neurogenetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus
5
Neurology Clinic C, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus
6
Neurology Clinic D, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors share the last authorship.
Int. J. Mol. Sci. 2018, 19(10), 3099; https://doi.org/10.3390/ijms19103099
Received: 14 August 2018 / Revised: 2 October 2018 / Accepted: 8 October 2018 / Published: 10 October 2018
(This article belongs to the Special Issue Bioactive Lipids and Lipidomics 2018)
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. View Full-Text
Keywords: GBA2; non-lysosomal β-glucosylceramidase; β-glucocerebrosidase; spastic ataxia; glucosylceramide; plasma membrane; lymphoblastoid cell lines GBA2; non-lysosomal β-glucosylceramidase; β-glucocerebrosidase; spastic ataxia; glucosylceramide; plasma membrane; lymphoblastoid cell lines
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MDPI and ACS Style

Malekkou, A.; Samarani, M.; Drousiotou, A.; Votsi, C.; Sonnino, S.; Pantzaris, M.; Chiricozzi, E.; Zamba-Papanicolaou, E.; Aureli, M.; Loberto, N.; Christodoulou, K. Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia. Int. J. Mol. Sci. 2018, 19, 3099. https://doi.org/10.3390/ijms19103099

AMA Style

Malekkou A, Samarani M, Drousiotou A, Votsi C, Sonnino S, Pantzaris M, Chiricozzi E, Zamba-Papanicolaou E, Aureli M, Loberto N, Christodoulou K. Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia. International Journal of Molecular Sciences. 2018; 19(10):3099. https://doi.org/10.3390/ijms19103099

Chicago/Turabian Style

Malekkou, Anna, Maura Samarani, Anthi Drousiotou, Christina Votsi, Sandro Sonnino, Marios Pantzaris, Elena Chiricozzi, Eleni Zamba-Papanicolaou, Massimo Aureli, Nicoletta Loberto, and Kyproula Christodoulou. 2018. "Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia" International Journal of Molecular Sciences 19, no. 10: 3099. https://doi.org/10.3390/ijms19103099

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