TY - JOUR
T1 - Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia
AU - Martin, Elodie
AU - Schüle, Rebecca
AU - Smets, Katrien
AU - Rastetter, Agnès
AU - Boukhris, Amir
AU - Loureiro, José L.
AU - Gonzalez, Michael A.
AU - Mundwiller, Emeline
AU - Deconinck, Tine
AU - Wessner, Marc
AU - Jornea, Ludmila
AU - Oteyza, Andrés Caballero
AU - Durr, Alexandra
AU - Martin, Jean Jacques
AU - Schöls, Ludger
AU - Mhiri, Chokri
AU - Lamari, Foudil
AU - Züchner, Stephan
AU - De Jonghe, Peter
AU - Kabashi, Edor
AU - Brice, Alexis
AU - Stevanin, Giovanni
N1 - Funding Information:
We are grateful to the family members for their participation. We would like to thank S. Ciura, M. Nawara, J. Gomez, P. Coutinho, I. Alonso, N. Jezequel, P. Touraine, G. Gyapay, V. Meyer, S. Rivaud-Péchoux, S. Forlani, and the DNA and Cell Bank of the Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière for their contribution to this study. We also thank F. Mochel, F. Darios, K.H. El-Hachimi, and R. Schiffmann for their advice and the clinicians and collaborators of the Spastic paraplegia and ataxia (SPATAX) network who referred to us some of the affected subjects. This work was supported by the Association Strumpell-Lorrain (to SPATAX), the Agence Nationale de la Recherche (ANR) (“SPAX” to A.D. and “LIGENAX” and “SPG11” to G.S.), the Association Française contre les Myopathies (“LIGENAX” to G.S.), the European Union and ANR through the Eranet E-Rare program (“EUROSPA” to A.B. and L.S.), the Deutsches Zentrum für Neurodegenerative Erkrankungen (to L.S.), the Interdisziplinären Zentrums für Klinische Forschung University of Tübingen (grant 1970-0-0 to R.S.), and the Verum foundation (to A.B.). This study also benefited from funding from the program “Investissements d’avenir” ANR-10-IAIHU-06 (to the Brain and Spine Institute, Paris).
PY - 2013/2/7
Y1 - 2013/2/7
N2 - Spastic paraplegia 46 refers to a locus mapped to chromosome 9 that accounts for a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP). With next-generation sequencing in three independent families, we identified four different mutations in GBA2 (three truncating variants and one missense variant), which were found to cosegregate with the disease and were absent in controls. GBA2 encodes a microsomal nonlysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide to free glucose and ceramide and the hydrolysis of bile acid 3-O-glucosides. The missense variant was also found at the homozygous state in a simplex subject in whom no residual glucocerebrosidase activity of GBA2 could be evidenced in blood cells, opening the way to a possible measurement of this enzyme activity in clinical practice. The overall phenotype was a complex HSP with mental impairment, cataract, and hypogonadism in males associated with various degrees of corpus callosum and cerebellar atrophy on brain imaging. Antisense morpholino oligonucleotides targeting the zebrafish GBA2 orthologous gene led to abnormal motor behavior and axonal shortening/branching of motoneurons that were rescued by the human wild-type mRNA but not by applying the same mRNA containing the missense mutation. This study highlights the role of ceramide metabolism in HSP pathology.
AB - Spastic paraplegia 46 refers to a locus mapped to chromosome 9 that accounts for a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP). With next-generation sequencing in three independent families, we identified four different mutations in GBA2 (three truncating variants and one missense variant), which were found to cosegregate with the disease and were absent in controls. GBA2 encodes a microsomal nonlysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide to free glucose and ceramide and the hydrolysis of bile acid 3-O-glucosides. The missense variant was also found at the homozygous state in a simplex subject in whom no residual glucocerebrosidase activity of GBA2 could be evidenced in blood cells, opening the way to a possible measurement of this enzyme activity in clinical practice. The overall phenotype was a complex HSP with mental impairment, cataract, and hypogonadism in males associated with various degrees of corpus callosum and cerebellar atrophy on brain imaging. Antisense morpholino oligonucleotides targeting the zebrafish GBA2 orthologous gene led to abnormal motor behavior and axonal shortening/branching of motoneurons that were rescued by the human wild-type mRNA but not by applying the same mRNA containing the missense mutation. This study highlights the role of ceramide metabolism in HSP pathology.
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U2 - 10.1016/j.ajhg.2012.11.021
DO - 10.1016/j.ajhg.2012.11.021
M3 - Article
C2 - 23332916
AN - SCOPUS:84873707921
VL - 92
SP - 238
EP - 244
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -