TY - JOUR
T1 - Developmental delay and late onset HBSL pathology in hypomorphic Dars1 M256L mice
AU - Klugmann, Matthias
AU - Kalotay, Elizabeth
AU - Delerue, Fabien
AU - Ittner, Lars M.
AU - Bongers, Andre
AU - Yu, Josephine
AU - Morris, Margaret J.
AU - Housley, Gary D.
AU - Fröhlich, Dominik
N1 - Funding Information:
We acknowledge the Transgenic core facility at Macquarie University (Genome Editing Macquarie - GEM) for generating the Dars1 mice. We acknowledge the facilities, and the scientific and technical assistance of the Histopathology and Organ Pathology Service, University of Melbourne, which is supported by Phenomics Australia (PA). PA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We also 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 Centre, Biological Imaging Resources Laboratory. In this context, we also thank Mr. Brendan Lee for his help with image acquisitions. M256L
Funding Information:
We acknowledge the Transgenic core facility at Macquarie University (Genome Editing Macquarie - GEM) for generating the Dars1M256Lmice. We acknowledge the facilities, and the scientific and technical assistance of the Histopathology and Organ Pathology Service, University of Melbourne, which is supported by Phenomics Australia (PA). PA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We also 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 Centre, Biological Imaging Resources Laboratory. In this context, we also thank Mr. Brendan Lee for his help with image acquisitions.
Funding Information:
This work was funded by the Medical Research Future Fund (MRFF-ARLKO) of the Australian Government / Department of Health, the European Leukodystrophy Association (ELA 2018-014I2) and the Mission Massimo Foundation.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7
Y1 - 2022/7
N2 - The leukodystrophy Hypomyelination with Brainstem and Spinal cord involvement and Leg spasticity (HBSL) is caused by recessive mutations of the DARS1 gene, which encodes the cytoplasmic aspartyl-tRNA synthetase. HBSL is a spectrum disorder with disease onset usually during early childhood and no available treatment options. Patients display regression of previously acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Gene-function studies in mice revealed that homozygous Dars1 deletion is embryonically lethal, suggesting that successful modelling of HBSL requires the generation of disease-causing genocopies in mice. In this study, we introduced the pathogenic DARS1M256L mutation located on exon nine of the murine Dars1 locus. Despite causing severe illness in humans, homozygous Dars1M256L mice were only mildly affected. To exacerbate HBSL symptoms, we bred Dars1M256L mice with Dars1-null ‘enhancer’ mice. The Dars1M256L/− offspring displayed increased embryonic lethality, severe developmental delay, reduced body weight and size, hydrocephalus, anophthalmia, and vacuolization of the white matter. Remarkably, the Dars1M256L/− genotype affected energy metabolism and peripheral organs more profoundly than the nervous system and resulted in reduced body fat, increased respiratory exchange ratio, reduced liver steatosis, and reduced hypocellularity of the bone marrow. In summary, homozygous Dars1M256L and compound heterozygous Dars1M256L/− mutation genotypes recapitulate some aspects of HBSL and primarily manifest in developmental delay as well as metabolic and peripheral changes. These aspects of the disease might have been overlooked in HBSL patients with severe neurological deficits but could be included in the differential diagnosis of HBSL in the future.
AB - The leukodystrophy Hypomyelination with Brainstem and Spinal cord involvement and Leg spasticity (HBSL) is caused by recessive mutations of the DARS1 gene, which encodes the cytoplasmic aspartyl-tRNA synthetase. HBSL is a spectrum disorder with disease onset usually during early childhood and no available treatment options. Patients display regression of previously acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Gene-function studies in mice revealed that homozygous Dars1 deletion is embryonically lethal, suggesting that successful modelling of HBSL requires the generation of disease-causing genocopies in mice. In this study, we introduced the pathogenic DARS1M256L mutation located on exon nine of the murine Dars1 locus. Despite causing severe illness in humans, homozygous Dars1M256L mice were only mildly affected. To exacerbate HBSL symptoms, we bred Dars1M256L mice with Dars1-null ‘enhancer’ mice. The Dars1M256L/− offspring displayed increased embryonic lethality, severe developmental delay, reduced body weight and size, hydrocephalus, anophthalmia, and vacuolization of the white matter. Remarkably, the Dars1M256L/− genotype affected energy metabolism and peripheral organs more profoundly than the nervous system and resulted in reduced body fat, increased respiratory exchange ratio, reduced liver steatosis, and reduced hypocellularity of the bone marrow. In summary, homozygous Dars1M256L and compound heterozygous Dars1M256L/− mutation genotypes recapitulate some aspects of HBSL and primarily manifest in developmental delay as well as metabolic and peripheral changes. These aspects of the disease might have been overlooked in HBSL patients with severe neurological deficits but could be included in the differential diagnosis of HBSL in the future.
KW - Aminoacyl-tRNA synthetase
KW - Aspartyl-tRNA synthetase
KW - DARS1
KW - HBSL
KW - Hypomyelination with brainstem and spinal cord involvement and Leg spasticity
KW - Leukodystrophy
UR - http://www.scopus.com/inward/record.url?scp=85127450670&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127450670&partnerID=8YFLogxK
U2 - 10.1007/s11064-022-03582-4
DO - 10.1007/s11064-022-03582-4
M3 - Article
C2 - 35357600
AN - SCOPUS:85127450670
SN - 0364-3190
VL - 47
SP - 1972
EP - 1984
JO - Neurochemical Research
JF - Neurochemical Research
IS - 7
ER -