A murine model lacking Lyst recapitulates Chediak-Higashi syndrome with an earlier-onset neurodegenerative phenotype.

Abstract

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by pathogenic variants in the lysosomal trafficking regulator (LYST) gene and characterized by significant immunological and neurological impairment. Current mouse models do not replicate the early-onset neurological symptoms of patients. We develop and characterize a CHS model lacking the Lyst gene (ΔLYST-B6) using CRISPR-Cas9. The ΔLYST-B6 mouse exhibits key CHS features, including partial oculocutaneous albinism, prolonged bleeding, and enlarged intracellular granules. Molecular analyses confirm LYST deficiency, with reduced Lyst mRNA and protein levels across various tissues. Histological examination reveals progressive cerebellar Purkinje cell loss and axonal degeneration in peripheral nerves. Importantly, the ΔLYST-B6 show significant neurological impairment by 6 months of age. Lipidomic and transcriptomic analyses highlight increased proinflammatory lipid levels and immune signaling, suggesting neuroinflammation in CHS pathology. The ΔLYST-B6 mouse provides a valuable tool for studying the underlying mechanisms of CHS-associated neurodegeneration and for developing potential therapeutic strategies.