Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity

• Published in: American journal of human genetics Vol. 92; no. 5; pp. 774 - 780
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.05.2013; Cell Press; Elsevier
• Subjects: Amino acids; Aspartate-tRNA Ligase - chemistry; Aspartate-tRNA Ligase - genetics; Brain Stem - pathology; Children & youth; Crystallography, X-Ray; Genomes; Humans; Leg - pathology; Leukoencephalopathies - genetics; Leukoencephalopathies - pathology; Medical treatment; Models, Molecular; Muscle Spasticity - genetics; Mutation; Mutation - genetics; Protein Conformation; Spinal Cord - pathology; Transfer RNA; Yeast
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2013.04.006

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.