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: Ryan J Taft, Adeline Vanderver, Richard J Leventer, Stephen A Damiani, Cas Simons, Sean M Grimmond, David Miller, Johanna Schmidt, Paul J Lockhart, Kate Pope, Kelin Ru, Joanna Crawford, Tena Rosser, Irenaeus F M de Coo, Monica Juneja, Ishwar C Verma, Prab Prabhakar, Susan Blaser, Julian Raiman, Petra J W Pouwels, Marianna R Bevova, Truus E M Abbink, Marjo S van der Knaap, Nicole I Wolf
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 92 Issue 5 Pg. 774-80 (May 02 2013) ISSN: 1537-6605 [Electronic] United States
• PMID: 23643384 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Aspartate-tRNA Ligase

Topics

• Aspartate-tRNA Ligase (chemistry, genetics)
• Brain Stem (pathology)
• Crystallography, X-Ray
• Humans
• Leg (pathology)
• Leukoencephalopathies (genetics, pathology)
• Models, Molecular
• Muscle Spasticity (genetics)
• Mutation (genetics)
• Protein Conformation
• Spinal Cord (pathology)