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Chediak-Higashi disease

Tuesday 6 September 2005

Affected patients with the Chédiak-Higashi syndrome have neurologic dysfunction and various immunologic deficits leading to life-threatening pyogenic infections. Chediak-Higashi disease is caused by LYST mutations at 1q42 (MIM.214500)

The cellular hallmarks of the Chédiak-Higashi syndrome include large lysosomal granules in leukocytes, giant melanosomes in melanocytes, a deficiency of neutrophil-mediated bactericidal activity, and loss of cytotoxicity of T cells and natural killer cells.

The giant melanosomes fail to mature normally and are subject to premature destruction through fusion with lysosomes, leading to pigmentary dilution and oculocutaneous albinism.

The loss of T-cell cytotoxicity is apparently due to the cells’ inability to secrete cytolytic proteins stored in the giant granules.

Etiology

Chediak-Higashi disease is caused by LYST mutations at 1q42 (MIM.214500). The LYST gene encodes a cytosolic protein named lysosomal-trafficking regulator.

The structure of this protein is similar to that of a well-characterized protein involved in vacuolar sorting in budding yeast, a model corresponding to lysosomal-protein transport in mammals.

This finding, together with the abnormal distribution of late endosomal or lysosomal proteins in cells from patients with the Chédiak-Higashi syndrome, is consistent with the idea that a primary defect in molecular sorting occurs in the Golgi apparatus or endosomes.

References

- Griffiths GM. Albinism and immunity: what’s the link? Curr Mol Med. 2002 Aug;2(5):479-83. PMID: #12125813#

- Olkkonen VM, Ikonen E. Genetic defects of intracellular-membrane transport. N Engl J Med. 2000 Oct 12;343(15):1095-104. PMID: #11027745#

- Barbosa MDSF, Nguyen QA, Tchernev VT, et al. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature 1996;382:262-265.