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

Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator (LYST) gene, characterized by partial oculocutaneous albinism, bleeding diathesis, immune deficiency, and progressive neurodegeneration. We generated a Lyst knockout model (?LYST-B6) in which to accurately study pathophysiology seen in patients. Here we show the ?LYST-B6 model faithfully recapitulates characteristic features of CHS, including neurological manifestations at 6 months of age with associated progressive loss of Purkinje cells. Transcriptomic and lipidomic analyses of ?LYST-B6 brain tissue reveals numerous differentially expressed genes and lipids in the cerebellum of 18-month-old ?LYST-B6 mice suggesting progressive cerebellar decline and microglial involvement. Immunofluorescence studies implicate a plausible role of Bergmann glia in the pathology of CHS. Our findings demonstrate that the ?LYST-B6 model recapitulates key features of the human CHS phenotype, including CHS-associated neurodegeneration, and provides a reliable model in which to study the function of LYST and explore future therapies for CHS. Overall design: A knockout mouse model (?LYST-B6) lacking a functional murine Lyst homologue was generated by deleting exons 4-53 using CRISPR/Cas9 gene editing on the C57BL/6J genetic background. To characterize the neurological phenotype of ?LYST-B6 mice, brain tissues (cerebellum and cortex) were collected from 3- and 18-month-old wildtype and ?LYST-B6 mice.