Journal Article

DZNE-2020-03125

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia.

Martin, E. ; Schüle, R. ; Smets, K. ; Rastetter, A. ; Boukhris, A. ; Loureiro, J. L. ; Gonzalez, M. A. ; Mundwiller, E. ; Deconinck, T. ; Wessner, M. ; Jornea, L. ; Oteyza, A. C. ; Durr, A. ; Martin, J.-J. ; Schöls, L.DZNE* ; Mhiri, C. ; Lamari, F. ; Züchner, S. ; De Jonghe, P. ; Kabashi, E. ; Brice, A. (Corresponding author) ; Stevanin, G.

2013
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.ajhg.2012.11.021

Abstract: 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.

Keyword(s): Adolescent (MeSH) ; Adult (MeSH) ; Aged (MeSH) ; Animals (MeSH) ; Brain: pathology (MeSH) ; Child (MeSH) ; Child, Preschool (MeSH) ; Family (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Infant (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Motor Neurons: pathology (MeSH) ; Mutation: genetics (MeSH) ; Neuroimaging (MeSH) ; Pedigree (MeSH) ; Spastic Paraplegia, Hereditary: enzymology (MeSH) ; Spastic Paraplegia, Hereditary: genetics (MeSH) ; Young Adult (MeSH) ; Zebrafish (MeSH) ; Zebrafish Proteins: genetics (MeSH) ; beta-Glucosidase: genetics (MeSH) ; Zebrafish Proteins ; beta-Glucosidase ; GBA2 protein, human ; GBA2 protein, zebrafish

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Contributing Institute(s):

1. Clinical Neurogenetics (AG Schöls)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2013

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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