Journal article

A Hypomorphic Dars1(D367Y) Model Recapitulates Key Aspects of the Leukodystrophy HBSL

Dominik Frohlich, Marisa I Mendes, Andrew J Kueh, Andre Bongers, Marco J Herold, Gajja S Salomons, Gary D Housley, Matthias Klugmann



Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) is a leukodystrophy caused by missense mutations of the aspartyl-tRNA synthetase-encoding gene DARS1. The clinical picture includes the regression of acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Morphologically, HBSL is characterized by a distinct pattern of hypomyelination in the central nervous system including the anterior brainstem, the cerebellar peduncles and the supratentorial white matter as well as the dorsal columns and the lateral corticospinal tracts of the spinal cord. Adequate HBSL animal models are lacking. Dars1 knockout mice are embryoni..

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Awarded by European Leukodystrophy Association

Funding Acknowledgements

This work was funded by the Medical Research Future Fund (MRFF-ARLKO), the European Leukodystrophy Association (ELA 2015-016I3 and ELA 2018-014I2) and the Mission Massimo Foundation. The MAGEC and the HOPS are supported by Phenomics Australia (PA; formerly known as Australian Phenomics Network) and PA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We acknowledge the facilities, and the scientific and technical assistance of the Melbourne Advanced Genome Editing Center (MAGEC) at the Walter and Eliza Hall Institute of Medical Research (WEHI) and the Histopathology and Organ Pathology Service (HOPS), University of Melbourne. We acknowledge the National Imaging Facility (NIF), Australia, for the financial support of MR imaging instrumentation, and the scientific and technical assistance at the UNSW NIF node, Mark Wainwright Analytical Center, Biological Imaging Resources Laboratory. In this context, we also thank Mr. Brendan Lee for his help with image acquisitions.