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@ARTICLE{Martin:136803,
author = {Martin, Elodie and Schüle, Rebecca and Smets, Katrien and
Rastetter, Agnès and Boukhris, Amir and Loureiro, José L
and Gonzalez, Michael A and Mundwiller, Emeline and
Deconinck, Tine and Wessner, Marc and Jornea, Ludmila and
Oteyza, Andrés Caballero and Durr, Alexandra and Martin,
Jean-Jacques and Schöls, Ludger and Mhiri, Chokri and
Lamari, Foudil and Züchner, Stephan and De Jonghe, Peter
and Kabashi, Edor and Brice, Alexis and Stevanin, Giovanni},
title = {{L}oss of function of glucocerebrosidase {GBA}2 is
responsible for motor neuron defects in hereditary spastic
paraplegia.},
journal = {The American journal of human genetics},
volume = {92},
number = {2},
issn = {0002-9297},
address = {New York, NY},
publisher = {Elsevier},
reportid = {DZNE-2020-03125},
pages = {238-244},
year = {2013},
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.},
keywords = {Adolescent / Adult / Aged / Animals / Brain: pathology /
Child / Child, Preschool / Family / Female / Humans / Infant
/ Male / Middle Aged / Motor Neurons: pathology / Mutation:
genetics / Neuroimaging / Pedigree / Spastic Paraplegia,
Hereditary: enzymology / Spastic Paraplegia, Hereditary:
genetics / Young Adult / Zebrafish / Zebrafish Proteins:
genetics / beta-Glucosidase: genetics / Zebrafish Proteins
(NLM Chemicals) / beta-Glucosidase (NLM Chemicals) / GBA2
protein, human (NLM Chemicals) / GBA2 protein, zebrafish
(NLM Chemicals)},
cin = {AG Schöls},
ddc = {570},
cid = {I:(DE-2719)5000005},
pnm = {345 - Population Studies and Genetics (POF3-345)},
pid = {G:(DE-HGF)POF3-345},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:23332916},
pmc = {pmc:PMC3567271},
doi = {10.1016/j.ajhg.2012.11.021},
url = {https://pub.dzne.de/record/136803},
}