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Clinical, Molecular, and Cell Biological Aspects of Chediak–Higashi Syndrome

https://doi.org/10.1006/mgme.1999.2927Get rights and content

Abstract

Chediak–Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by variable degrees of oculocutaneous albinism, easy bruisability, and bleeding as a result of deficient platelet dense bodies, and recurrent infections, with neutropenia, impaired chemotaxis and bactericidal activity, and abnormal NK cell function. Neurologic involvement is variable, but often includes peripheral neuropathy. Most patients also undergo an “accelerated phase,” which is a nonmalignant lymphohistiocytic infiltration of multiple organs resembling lymphoma. Death often occurs in the first decade from infection, bleeding, or development of the accelerated phase. The hallmark of CHS is the presence of huge cytoplasmic granules in circulating granulocytes and many other cell types. These granules are peroxidase-positive and contain lysosomal enzymes, suggesting that they are giant lysosomes or, in the case of melanocytes, giant melanosomes. The underlying defect in CHS remains elusive, but the disorder can be considered a model for defects in vesicle formation, fusion, or trafficking. Because the beige mouse demonstrates many characteristics similar to those of human CHS patients, including dilution of coat color, recurrent infections, and the presence of giant granules, it is considered the animal homologue of CHS. The beige gene, Lyst, was mapped and sequenced in 1996, prompting identification of the human LYST gene on chromosome 1q42. Lyst and LYST show 86.5% sequence homology. LYST encodes a 429 kDa protein with a function that remains unknown, but the source of extensive speculation among students of cell biology.

References (145)

  • LJ Engle et al.

    Cloning, analysis, and chromosomal localization of myoxin (MYH12), the human homologue to the mouse dilute gene

    Genomics

    (1994)
  • SM Garay et al.

    Hermansky–Pudlak Syndrome: Pulmonary manifestations of a ceroid storage disorder

    Am J Med

    (1979)
  • T Bailin et al.

    Organization and nucleotide sequence of the human Hermansky–Pudlak syndrome (HPS) gene

    J Invest Dermatol

    (1997)
  • V Shotelersuk et al.

    Three new mutations in a gene causing Hermansky–Pudlak syndrome: Clinical correlations

    Mol Genet Metab

    (1998)
  • J Oh et al.

    Mutation analysis of patients with Hermansky–Pudlak syndrome: A frameshift hot spot in the HPS gene and apparent locus heterogeneity

    Am J Hum Genet.

    (1998)
  • S Hazelwood et al.

    Evidence for locus heterogeneity in Puerto Ricans with Hermansky-Pudlak syndrome

    Am J Hum Genet

    (1997)
  • EC Dell'Angelica et al.

    Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the β3A subunit of the AP-3 adaptor

    Mol Cell

    (1999)
  • EC Dell'Angelica et al.

    β3A-adaptin, a subunit of the adaptor-like complex AP-3

    J Biol Chem

    (1997)
  • RS Weening et al.

    Effect of ascorbate on abnormal neutrophil, platelet, and lymphocyte function in a patient with the Chediak–Higashi syndrome

    Blood

    (1981)
  • JI Gallin et al.

    Efficacy of ascorbic acid in Chediak–Higashi syndrome (CHS): Studies in humans and mice

    Blood

    (1979)
  • J Kazmierowski et al.

    Chediak–Higashi syndrome: Reversal of increased susceptibility to infection by bone marrow transplantation

    Blood

    (1976)
  • E Haddad et al.

    Treatment of Chediak–Higashi syndrome by allogenic bone marrow transplantation: Report of 10 cases

    Blood

    (1995)
  • RW Leader et al.

    Studies of abnormal leukocyte bodies in mink

    Blood

    (1963)
  • EK Novak et al.

    Platelet storage pool deficiency in mouse pigment mutations associated with seven distinct genetic loci

    Blood

    (1984)
  • EK Novak et al.

    Correction of symptoms of platelet storage pool deficiency in animal models for Chediak–Higashi syndrome and Hermansky–Pudlak syndrome

    Blood

    (1985)
  • JI Gallin et al.

    Granulocyte function in the Chediak–Higashi syndrome of mice

    Blood

    (1974)
  • DJ Misumi et al.

    The physical and genetic map surrounding the Lyst gene on mouse chromosome 13

    Genomics

    (1997)
  • M Peifer et al.

    A repeating amino acid motif shared by proteins with diverse cellular roles

    Cell

    (1994)
  • M DiFiglia et al.

    Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons

    Neuron

    (1995)
  • DM Sabatini et al.

    RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs

    Cell

    (1994)
  • XF Zheng et al.

    TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin

    Cell

    (1995)
  • AB Beguez-Cesar

    Neutropenia cronica maligna familiar con granulaciones atipicas de los leucocitos

    Bol Soc Cubana Pediatr

    (1943)
  • W Steinbrinck

    Uber eine neue Granulationsanomalie der Leukocyten

    Dtsch Arch Klin Med

    (1948)
  • M Chediak

    Nouvelle anomalie leukocytaire de caractere constitutionnel et familiel

    Rev Hematol

    (1952)
  • O Higashi

    Congenital gigantism of peroxidase granules

    Tohoku J Exp Med

    (1954)
  • CJ Witkop et al.

    Albinism

  • RA King et al.

    Albinism

  • DL Nagle et al.

    Identification and mutation analysis of the complete gene for Chediak–Higashi syndrome

    Nat Genet

    (1996)
  • RS Blume et al.

    The Chediak–Higashi syndrome: studies in four patients and a review of the literature

    Medicine

    (1972)
  • R Apitz-Castro et al.

    The storage pool deficiency in platelets from humans with the Chediak–Higashi syndrome: Study of six patients

    Br J Haematol

    (1985)
  • R Valenzuela et al.

    Chediak–Higashi syndrome in a black infant: A light and electron microscopic study with special emphasis on erythrophagocytosis

    Am J Clin Path

    (1976)
  • HA de Beer et al.

    Chediak–Higashi syndrome in a “black” child

    S Afr Med J

    (1981)
  • H Zhao et al.

    On the analysis of the pathophysiology of Chediak–Higashi syndrome: Defects expressed by cultured melanocytes

    Lab Invest

    (1994)
  • R Valenzuela et al.

    The ocular pigmentary disturbance of human Chediak–Higashi syndrome. A comparative light- and electron-microscopic study and review of the literature

    Am J Clin Pathol

    (1981)
  • D BenEzra et al.

    Chediak–Higashi Syndrome: Ocular findings

    J Pediatr Ophthalmol Strabis

    (1980)
  • F Rendu et al.

    Evidence that abnormal platelet functions in human Chediak–Higashi syndrome are the result of a lack of dense bodies

    Am J Pathol

    (1983)
  • H Holmsen et al.

    Secretable storage pools in platelets

    Ann Rev Med

    (1979)
  • RT Parmley et al.

    Giant platelet granules in a child with the Chediak–Higashi syndrome

    Am J Hematol

    (1979)
  • JG White et al.

    Ultrastructural features of abnormal blood platelets

    Am J Pathol

    (1976)
  • RK Root et al.

    Abnormal bactericidal, metabolic, and lysosomal functions of Chediak–Higashi syndrome leukocytes

    J Clin Invest

    (1972)
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      Citation Excerpt :

      Similar functions are exerted by the LRBA protein homologue LYST (lysosomal trafficking regulator) [61]. Biallelic mutations in LYST cause a PID known as Chediak-Higashi syndrome (CHS) [62], which in contrast to LRBA deficiency does not present with immune dysregulation features, suggesting that LRBA and LYST act in different vesicle trafficking pathways with cellular specificity. Therefore, protein compensation by other LRBA homologues in LRBA-deficient patients with less severe clinical phenotype might be interesting to address.

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