Tuesday 6 September 2005
Chediak-Higashi syndrome is an autosomal recessive disorder caused by mutation of the lysosomal trafficking regulator protein. Phagolysosomes and melanosomes are dysfunctional, resulting in pyogenic infections, oculocutaneous albinism and peripheral neuropathy. Dohle bodies may be found in PMNS, and bone marrow biopsy shows inclusions in leukocyte precursors.
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.
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.
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