Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia.

Elodie Martin, Rebecca Schüle, Katrien Smets, Agnès Rastetter, Amir Boukhris, José L. Loureiro, Michael A. Gonzalez, Emeline Mundwiller, Tine Deconinck, Marc Wessner, Ludmila Jornea, Andrés Caballero Oteyza, Alexandra Durr, Jean-Jacques Martin, Ludger Schöls, Chokri Mhiri, Foudil Lamari, Stephan Züchner, Peter De Jonghe, Edor Kabashi, Alexis Brice, Giovanni Stevanin
The American Journal of Human Genetics. 2013-02-01; 92(2): 238-244
DOI: 10.1016/j.ajhg.2012.11.021

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1. Am J Hum Genet. 2013 Feb 7;92(2):238-44. doi: 10.1016/j.ajhg.2012.11.021. Epub
2013 Jan 17.

Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron
defects in hereditary spastic paraplegia.

Martin E(1), Schüle R, Smets K, Rastetter A, Boukhris A, Loureiro JL, Gonzalez
MA, Mundwiller E, Deconinck T, Wessner M, Jornea L, Oteyza AC, Durr A, Martin JJ,
Schöls L, Mhiri C, Lamari F, Züchner S, De Jonghe P, Kabashi E, Brice A, Stevanin

Author information:
(1)Unité Mixte de Recherche S975, Centre de Recherche de l’Institut du Cerveau et
de la Moelle Epinière, Pitie-Salpêtrière Hospital, Université Pierre et Marie
Curie (Paris 6), Paris, France.

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.

Copyright © 2013 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.

DOI: 10.1016/j.ajhg.2012.11.021
PMCID: PMC3567271
PMID: 23332916 [Indexed for MEDLINE]

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