Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Biochemistry

Background:

• Leukodystrophies are severe, progressive neurodevelopmental disorders often leading to premature death.
• Aminoacyl-t-RNA synthetase (ARS) gene abnormalities are increasingly linked to leukodystrophies and leukoencephalopathies.
• ARS enzymes are crucial for protein synthesis but can have non-canonical roles in transcription and translation.

Observation:

• Seven patients from five families presented with severe developmental delay, hypotonia, deafness, and inability to speak.
• Progressive symptoms included intractable epilepsy and nystagmus, alongside characteristic metabolic (lactate/pyruvate) and neuroimaging findings (white matter calcification/abnormalities).
• Whole-exome sequencing identified novel pathogenic variants in the lysyl-tRNA synthetase (KARS) gene in all affected individuals.

Findings:

• All patients harbored homozygous or compound heterozygous KARS variants, including a recurrent [c.1786C>T, p.Leu596Phe] mutation.
• Disrupted lysyl-tRNA synthetase (LysRS) proteins exhibited reduced enzymatic activity and abnormal central nervous system development in Xenopus models.
• LysRS demonstrated non-canonical roles as an immune response inducer and in transcriptional regulation.

Implications:

• Pathogenic KARS variants, particularly the recurrent [c.1786C>T, p.Leu596Phe] mutation, are strongly associated with severe progressive leukodystrophy.
• The complex, non-canonical functions of LysRS likely contribute to the severe neurological phenotypes observed in patients.
• Further research into KARS-related diseases is warranted to understand the spectrum of KARS-associated disorders and potential therapeutic targets.