LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is an autosomal recessive white matter disorder with slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction. Magnetic resonance imaging shows characteristic abnormalities in the cerebral white matter and specific brain stem and spinal cord tracts. LBSL is caused by mutations in the gene DARS2, which encodes mtAspRS (mitochondrial aspartyl-tRNA synthetase). The selective involvement of specific white matter tracts in LBSL is striking since this protein is ubiquitously expressed. Almost all LBSL patients have one mutation in intron 2 of DARS2, affecting the splicing of the third exon. Using a splicing reporter construct, we find cell-type-specific differences in the sensitivity to these mutations: the mutations have a larger effect on exon 3 exclusion in neural cell lines, especially neuronal cell lines, than in non-neural cell lines. Furthermore, correct inclusion of exon 3 in the normal mtAspRS mRNA occurs less efficiently in neural cells than in other cell types, and this effect is again most pronounced in neuronal cells. The combined result of these two effects may explain the selective vulnerability of specific white matter tracts in LBSL patients.
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February 2012
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Research Article|
January 16 2012
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA
Laura van Berge
;
Laura van Berge
1
1Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
1To whom correspondence should be addressed (email l.vanberge@vumc.nl).
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Stephanie Dooves
;
Stephanie Dooves
1Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
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Carola G.M. van Berkel
;
Carola G.M. van Berkel
1Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
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Emiel Polder
;
Emiel Polder
1Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
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Marjo S. van der Knaap
;
Marjo S. van der Knaap
1Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
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Gert C. Scheper
Gert C. Scheper
1Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
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Biochem J (2012) 441 (3): 955–962.
Article history
Received:
May 09 2011
Revision Received:
September 23 2011
Accepted:
October 25 2011
Accepted Manuscript online:
October 25 2011
Citation
Laura van Berge, Stephanie Dooves, Carola G.M. van Berkel, Emiel Polder, Marjo S. van der Knaap, Gert C. Scheper; Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA. Biochem J 1 February 2012; 441 (3): 955–962. doi: https://doi.org/10.1042/BJ20110795
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