Genetic and Cellular Mechanisms in Chediak-Higashi Syndrome

Chediak-Higashi syndrome is an autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator gene, LYST, which encodes a large cytosolic protein essential for the regulation of lysosome and lysosome-related organelle biogenesis and dynamics. Loss of LYST function leads to the formation of giant lysosomal compartments in a range of cell types, notably cytotoxic lymphocytes, melanocytes and phagocytes, resulting in defective granule exocytosis, pigment dilution and impaired microbial killing. Clinically, patients present with oculocutaneous albinism, recurrent infections, bleeding diathesis and an often fatal haemophagocytic lymphohistiocytosis owing to uncontrolled immune activation. At the cellular level, enlarged lysosomes exhibit disrupted membrane fission–fusion balance, altered pH regulation and impaired interaction with the actin cytoskeleton, which together compromise vesicle trafficking, immune synapse formation and secretion of lytic enzymes. Modifier genes and genetic background influence the severity of neurological dysfunction seen in murine models, highlighting the interplay between LYST-dependent pathways and oxidative stress in neurodegeneration. Advances in genome sequencing have expanded the spectrum of pathogenic LYST variants and revealed associations with attenuated phenotypes and late-onset neurodegeneration, underscoring the complexity of genotype–phenotype correlations and opening avenues for targeted genetic diagnosis and counselling.

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Genetic and Cellular Mechanisms in Chediak-Higashi Syndrome publication trend

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Technical terms

LYST: Lysosomal trafficking regulator protein that governs membrane fission–fusion events and organelle size.

Lysosome: Intracellular organelle containing hydrolytic enzymes for degradation of macromolecules.

Lysosome-related organelles (LROs): Specialised vesicles derived from endolysosomal pathways that carry cell-type-specific cargo.

Phagosome: Vesicle formed around particles or pathogens internalised by phagocytosis, which subsequently fuses with lysosomes.

Haemophagocytic lymphohistiocytosis (HLH): A severe hyperinflammatory syndrome resulting from unchecked activation of lymphocytes and macrophages.

References

1. The lysosomal trafficking regulator “LYST”: an 80-year traffic jam. Frontiers in Immunology (2024).
2. An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome. Journal of Allergy and Clinical Immunology (2017).
3. The Beige/Chediak-Higashi Syndrome Gene Encodes a Widely Expressed Cytosolic Protein*. Journal of Biological Chemistry (1997).
4. The Chediak-Higashi Protein Interacts with SNARE Complex and Signal Transduction Proteins. Molecular Medicine (2002).
5. Towards the targeted management of Chediak-Higashi syndrome. Orphanet Journal of Rare Diseases (2014).
6. Elevated Oxidative Membrane Damage Associated with Genetic Modifiers of Lyst-Mutant Phenotypes. PLOS Genetics (2010).
7. Mouse models and strain-dependency of Chédiak-Higashi syndrome-associated neurologic dysfunction. Scientific Reports (2019).
8. Atypical Chédiak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease. Orphanet Journal of Rare Diseases (2013).
9. Whole Genome Sequencing Identifies Novel Compound Heterozygous Lysosomal Trafficking Regulator Gene Mutations Associated with Autosomal Recessive Chediak-Higashi Syndrome. Scientific Reports (2017).
10. Mauve/LYST limits fusion of lysosome-related organelles and promotes centrosomal recruitment of microtubule nucleating proteins. Developmental Cell (2021).
11. Deficiency in Lyst function leads to accumulation of secreted proteases and reduced retinal adhesion. PLOS ONE (2022).