TY  - JOUR
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
TI  - Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia.
JO  - The American journal of human genetics
VL  - 92
IS  - 2
SN  - 0002-9297
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2020-03125
SP  - 238-244
PY  - 2013
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.
KW  - Adolescent
KW  - Adult
KW  - Aged
KW  - Animals
KW  - Brain: pathology
KW  - Child
KW  - Child, Preschool
KW  - Family
KW  - Female
KW  - Humans
KW  - Infant
KW  - Male
KW  - Middle Aged
KW  - Motor Neurons: pathology
KW  - Mutation: genetics
KW  - Neuroimaging
KW  - Pedigree
KW  - Spastic Paraplegia, Hereditary: enzymology
KW  - Spastic Paraplegia, Hereditary: genetics
KW  - Young Adult
KW  - Zebrafish
KW  - Zebrafish Proteins: genetics
KW  - beta-Glucosidase: genetics
KW  - Zebrafish Proteins (NLM Chemicals)
KW  - beta-Glucosidase (NLM Chemicals)
KW  - GBA2 protein, human (NLM Chemicals)
KW  - GBA2 protein, zebrafish (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23332916
C2  - pmc:PMC3567271
DO  - DOI:10.1016/j.ajhg.2012.11.021
UR  - https://pub.dzne.de/record/136803
ER  -