title: Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity.
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.
authors: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia. r.taft@imb.uq.edu.au
authors: Ryan J
authors: RJ
authors: Taft
authors: Adeline
authors: A
authors: Vanderver
authors: Richard J
authors: RJ
authors: Leventer
authors: Stephen A
authors: SA
authors: Damiani
authors: Cas
authors: C
authors: Simons
authors: Sean M
authors: SM
authors: Grimmond
authors: David
authors: D
authors: Miller
authors: Johanna
authors: J
authors: Schmidt
authors: Paul J
authors: PJ
authors: Lockhart
authors: Kate
authors: K
authors: Pope
authors: Kelin
authors: K
authors: Ru
authors: Joanna
authors: J
authors: Crawford
authors: Tena
authors: T
authors: Rosser
authors: Irenaeus F M
authors: IF
authors: de Coo
authors: Monica
authors: M
authors: Juneja
authors: Ishwar C
authors: IC
authors: Verma
authors: Prab
authors: P
authors: Prabhakar
authors: Susan
authors: S
authors: Blaser
authors: Julian
authors: J
authors: Raiman
authors: Petra J W
authors: PJ
authors: Pouwels
authors: Marianna R
authors: MR
authors: Bevova
authors: Truus E M
authors: TE
authors: Abbink
authors: Marjo S
authors: MS
authors: van der Knaap
authors: Nicole I
authors: NI
authors: Wolf
mesh_terms: D001226:Aspartate-tRNA Ligase / Q000737:chemistry / Q000235:genetics*; D001933:Brain Stem / Q000473:pathology; D018360:Crystallography, X-Ray; D006801:Humans; D007866:Leg / Q000473:pathology; D056784:Leukoencephalopathies / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D009128:Muscle Spasticity / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D013116:Spinal Cord / Q000473:pathology
chemical_list: D001226:Aspartate-tRNA Ligase
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