Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity

Taft, Ryan J., Vanderver, Adeline, Leventer, Richard J., Damiani, Stephen A., Simons, Cas, Grimmond, Sean M., Miller, David, Schmidt, Johanna, Lockhart, Paul J., Pope, Kate, Ru, Kelin, Crawford, Joanna, Rosser, Tena, de Coo, Irenaeus F. M., Juneja, Monica, Verma, Ishwar C., Prabhakar, Prab, Blaser, Susan, Raiman, Julian, Pouwels, Petra J. W., Bevova, Marianna R., Abbink, Truus E. M., van der Knaap, Marjo S. and Wolf, Nicole I. (2013) Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. American Journal of Human Genetics, 92 5: 774-780. doi:10.1016/j.ajhg.2013.04.006


 
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Author Taft, Ryan J.
Vanderver, Adeline
Leventer, Richard J.
Damiani, Stephen A.
Simons, Cas
Grimmond, Sean M.
Miller, David
Schmidt, Johanna
Lockhart, Paul J.
Pope, Kate
Ru, Kelin
Crawford, Joanna
Rosser, Tena
de Coo, Irenaeus F. M.
Juneja, Monica
Verma, Ishwar C.
Prabhakar, Prab
Blaser, Susan
Raiman, Julian
Pouwels, Petra J. W.
Bevova, Marianna R.
Abbink, Truus E. M.
van der Knaap, Marjo S.
Wolf, Nicole I.
Title Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity
Formatted title
Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2013-05-02
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2013.04.006
Volume 92
Issue 5
Start page 774
End page 780
Total pages 7
Place of publication United States
Publisher Cell Press
Collection year 2014
Language eng
Formatted abstract
Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL), which is caused by mutations in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders.
Keyword Transfer-RNA-synthetase
Marie-Tooth-disease
DNA-sequencing data
Lactate elevation
Perrault syndrome
Hearing-loss
Leukoencephalopathy
Aminoacylation
Framework
Gene
Charcot-Marie-Tooth disease
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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