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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  DARS1   M256L   mutation located on exon nine of the murine  Dars1  locus. Despite causing severe illness in humans, homozygous  Dars1   M256L   mice were only mildly affected. To exacerbate HBSL symptoms, we bred  Dars1   M256L   mice with  Dars1 -null ‘enhancer’ mice. The  Dars1   M256L/−   offspring displayed increased embryonic lethality, severe developmental delay, reduced body weight and size, hydrocephalus, anophthalmia, and vacuolization of the white matter. Remarkably, the  Dars1   M256L/−   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  Dars1   M256L   and compound heterozygous  Dars1   M256L/−   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.

Developmental delay and late onset HBSL pathology in hypomorphic Dars1M256L mice