TY - JOUR
T1 - Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation
AU - Scheper, Gert C.
AU - Van Der Klok, Thom
AU - Van Andel, Rob J.
AU - Van Berkel, Carola G M
AU - Sissler, Marie
AU - Smet, Joél
AU - Muravina, Tatjana I.
AU - Serkov, Sergey V.
AU - Uziel, Graziella
AU - Bugiani, Marianna
AU - Schiffmann, Raphael
AU - Krägeloh-Mann, Ingeborg
AU - Smeitink, Jan A M
AU - Florentz, Catherine
AU - Van Coster, Rudy
AU - Pronk, Jan C.
AU - Van Der Knaap, Marjo S.
PY - 2007/4
Y1 - 2007/4
N2 - Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) has recently been defined based on a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. LBSL is an autosomal recessive disease, most often manifesting in early childhood. Affected individuals develop slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. We performed linkage mapping with microsatellite markers in LBSL families and found a candidate region on chromosome 1, which we narrowed by means of shared haplotypes. Sequencing of genes in this candidate region uncovered mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals from all 30 families. Enzyme activities of mutant proteins were decreased. We were surprised to find that activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays.
AB - Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) has recently been defined based on a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. LBSL is an autosomal recessive disease, most often manifesting in early childhood. Affected individuals develop slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. We performed linkage mapping with microsatellite markers in LBSL families and found a candidate region on chromosome 1, which we narrowed by means of shared haplotypes. Sequencing of genes in this candidate region uncovered mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals from all 30 families. Enzyme activities of mutant proteins were decreased. We were surprised to find that activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays.
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U2 - 10.1038/ng2013
DO - 10.1038/ng2013
M3 - Article
C2 - 17384640
AN - SCOPUS:34047109743
VL - 39
SP - 534
EP - 539
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 4
ER -