Molecular Genetics of Chediak–Higashi Syndrome

Abstract

Chediak–Higashi syndrome (CHS) is an autosomal recessive disorder associated with the formation of enlarged lysosomes and lysosome‐related organelles (LROs) clustered near the perinuclear region of cells. Affected vesicles include lysosomes, cytolytic granules, melanosomes and platelet dense granules. The enlarged vesicles give rise to decreased bacterial killing, partial albinism, defective wound repair, impaired coagulation and neurological problems. Patients succumb to untreated recurrent bacterial infections or a lymphoma‐like infiltration into the major organs of the body. Treatment for the disorder is prophylactic antibiotics followed by bone marrow transplant although pigmentation and neurological problems persist. The mutant gene, termed Lyst, responsible for CHS is present in all eukaryotes and model organisms have been utilised to try to determine the function of Lyst. The biochemical function of Lyst has not been resolved but Lyst has been proposed to be involved in regulating lysosome/LRO size by either controlling vesicle fusion or fission.

Key Concepts:

  • Chediak–Higashi syndrome (CHS) is a lethal disorder with patients succumbing to pathogen infections if not treated with antibiotics.

  • CHS patients show multiorgan dysfunction due to enlarged lysosome‐related organelles in all cells of the body.

  • Treatment for CHS is bone marrow transplant, although neurological problems remain.

  • The mutant gene responsible for CHS is Lyst, a highly conserved gene present in all eukaryotes.

  • Lyst is a member of a family of proteins, BEACH, involved in vesicle trafficking.

  • Regulating lysosome/LRO size is important for normal cellular processes including pigmentation, coagulation, wound repair and immune function.

Keywords: lysosome; vesicle; granule; Lyst; accelerated phase; membrane trafficking

Figure 1.

Microscopic analysis of the hair shaft, polymorphonuclear neutrophils and platelets from control and CHS patients. (a) Control hair shows pigment that is evenly distributed throughout the shaft. (b) Hair of a patient with classic Chediak–Higashi syndrome (CHS) shows an irregular distribution of large and small pigment clumps. (c) Normal control polymorphonuclear neutrophils (PMNs) harbour numerous small cytoplasmic granules. (d) The blood smear derived from a patient with classic severe CHS shows PMNs that contain enlarged intracytoplasmic granules, whereas (e) PMNs from an adult‐onset mildly affected patient contain many granules that are larger than normal but smaller than those of the patient with classic CHS. (f) Whole mount electron microscopy of control platelets shows several dense bodies per platelet (arrows), whereas (g) some CHS platelets have no dense bodies (asterisk) and others have irregular electron‐dense granules (arrows). Reproduced from Introne et al. (2009). © 1993–2013, University of Washington, Seattle. All rights reserved.

Figure 2.

Beige bone marrow‐derived macrophages show enlarged perinuclear lysosomes. Bone marrow‐derived macrophages from C57BL/6 and beigej mice were grown on glass coverslips in RPMI medium (Invitrogen, Carlsbad, CA), 2 mM l‐glutamine, 20 µM supplemented with 20% fetal bovine serum and 30% L‐cell conditioned medium. Cells were incubated with Alexa 594 dextran (mw 10 000) at 37 °C overnight followed by a 2 h chase to allow all dextran to localise to lysosomes. Images were captured on an Olympus BX51 upright microscope with a 60×1.4NA objective and PICTUREFRAMER software (Olympus).

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Kaplan, Jerry, and Ward, Diane M(Sep 2013) Molecular Genetics of Chediak–Higashi Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024308]