Journal article
Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity
RJ Taft, A Vanderver, RJ Leventer, SA Damiani, C Simons, SM Grimmond, D Miller, J Schmidt, PJ Lockhart, K Pope, K Ru, J Crawford, T Rosser, IFM De Coo, M Juneja, IC Verma, P Prabhakar, S Blaser, J Raiman, PJW Pouwels Show all
American Journal of Human Genetics | Published : 2013
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 highl..
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Awarded by National Institutes of Health
Funding Acknowledgements
We are grateful for the support and cooperation of the subjects with hypomyelination with brain stem and spinal cord involvement and leg spasticity, as well as their families. We wish to thank Illumina for their reagent contributions and continuous support of this project. We also thank Dennis Gascoigne and Michael Pheasant for their early support of this work and data-analysis advice, as well as David Amor of the Victorian Clinical Genetics Services. We are indebted to Emiel Polder and Nienke Postma for their help with DARS sequencing and to Marianna Bugiani for discussions on DABS expression. R.J.T. is supported by an Australian Research Council Discovery Early Career Research Award and is a consultant to Isis Pharmaceuticals. A.V. is supported by a grant from the National Institute of Neurologic Disorders and Stroke, National Institutes of Health (1K08NS060695) and by the Myelin Disorders Bioregistry Project. This work was supported by the Mission Massimo Foundation, the Victorian State Government Operational Infrastructure Support Program, the Institute for Molecular Bioscience funds, the NeCTAR Genomics Virtual Lab, a University of Queensland Foundation Research Excellence Award, and ZonMw TOP grant 91211005.