Developmental delay and late onset HBSL pathology in hypomorphic Dars1(M256L) mice

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.

Automated summary

This study identifies the phenotypes of the DARS1(M256L) mutation genotype associated with HBSL in mice, providing an important model for further study of HBSL.