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.
| Original language | English |
|---|---|
| Pages (from-to) | 238-244 |
| Number of pages | 7 |
| Journal | American Journal of Human Genetics |
| Volume | 92 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 7 2013 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. / Martin, Elodie; Schüle, Rebecca; Smets, Katrien; Rastetter, Agnès; Boukhris, Amir; Loureiro, José L.; Gonzalez, Michael A.; Mundwiller, Emeline; Deconinck, Tine; Wessner, Marc; Jornea, Ludmila; Oteyza, Andrés Caballero; Durr, Alexandra; Martin, Jean Jacques; Schöls, Ludger; Mhiri, Chokri; Lamari, Foudil; Zuchner, Stephan L; De Jonghe, Peter; Kabashi, Edor; Brice, Alexis; Stevanin, Giovanni.
In: American Journal of Human Genetics, Vol. 92, No. 2, 07.02.2013, p. 238-244.Research output: Contribution to journal › Article
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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 - Zuchner, Stephan L
AU - De Jonghe, Peter
AU - Kabashi, Edor
AU - Brice, Alexis
AU - Stevanin, Giovanni
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.
UR - http://www.scopus.com/inward/record.url?scp=84873707921&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873707921&partnerID=8YFLogxK
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 -