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 KabashiAlexis Brice, Giovanni Stevanin

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)238-244
Number of pages7
JournalAmerican journal of human genetics
Issue number2
StatePublished - Feb 7 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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