• Antigen presentation;
  • beige;
  • Chediak–Higashi;
  • Fusion;
  • Lysosome;
  • Trafficking;
  • Vesicle


  1. Top of page
  2. Abstract
  5. Acknowledgements
  6. References

Chediak–Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects including recurrent bacterial infections, impaired chemotaxis and abnormal natural killer (NK) cell function. Patients with this syndrome exhibit other symptoms such as an associated lymphoproliferative syndrome, bleeding tendencies, partial albinism and peripheral neuropathies. The classic diagnostic feature of CHS is the presence of huge lysosomes and cytoplasmic granules within cells. Similar defects are found in other mammals, the most well studied being the beige mouse and Aleutian mink. A positional cloning approach resulted in the identification of the Beige gene on chromosome 13 in mice and the CHS1/LYST gene on chromosome 1 in humans. The protein encoded by this gene is 3801 amino acids and is highly conserved throughout evolution. The identification of CHS1/Beige has defined a family of genes containing a common BEACH motif. The function of these proteins in vesicular trafficking remains unknown.


Chediak–Higashi Syndrome


cytolytic T lymphocytes


Hermansky–Pudlak Syndrome


natural killer


polymorphonuclear leucocyte


protein kinase C


  1. Top of page
  2. Abstract
  5. Acknowledgements
  6. References

Chediak–Higashi Syndrome (CHS) is a very rare autosomal recessive disorder. The syndrome is characterized by severe immune deficiency, oculocutaneous albinism, bleeding tendencies, recurrent pyogenic infection, progressive neurologic defects and a lymphoproliferative syndrome (1–3). The classic diagnostic feature of the syndrome is the presence of giant granules within various cells of the body (Fig. 1). These granules include vesicles such as lysosomes, melanosomes, cytolytic granules and platelet dense bodies. The fact that all of these organelles are affected suggests a common origin or regulation mechanism in their biogenesis. There are different organellar diseases in humans that affect lysosomes, melanosomes, cytolytic granules and platelet dense bodies (Table 1 (4–6). Some of the identified mutant genes have functions relating to vesicular trafficking. Other protein functions, such as Hermansky–Pudlak Syndrome (HPS)-1, remain to be elucidated. The gene responsible for CHS was cloned in 1996 (7–11). However, the function of the protein remains unknown. This review will describe some of the clinical features of this disease, the cloning of the CHS gene and homologs in other species, the cellular defects associated with the disease and the possible role CHS plays in vesicle formation and maintenance.


Figure 1. . Lysosome morphology in human wild type (HSFWll) and CHS (GM02075) fibroblasts. Fibroblasts were cultured in DMEM with 10% fetal bovine serum. Cells were incubated with 0.1 mg/ml Texas Red dextran at 37°C for 12 h, washed and incubated in culture medium for an additional 2 h prior to imaging. The Texas Red dextran will label only lysosomes. Images were captured using a 100× oil immersion objective on a Nikon inverted microscope run by a Macintosh workstation using OpenLab software.

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Table 1.  . Human diseases that affect lysosomes and lysosome-related organelles Thumbnail image of

Clinical Features of CHS

The diagnosis of CHS is usually correlated with the presence of hypopigmentation and frequent, sometimes fatal, pyogenic bacterial infections. The skin, hair and eye pigmentation may be altered. Hypopigmentation of the eyes can result in photophobia and decreased visual acuity (12–14). Cells are capable of making pigment and the pigment is present in melanosomes; however, the melanosomes are abnormally large (15, 16). It is thought that the increased size of the melanosomes inhibits their migration to the cell surface and they are therefore unable to release their contents for absorption by the keratinocytes.

CHS patients may show a mild coagulation defect with bruising, mucosal bleeding and petechiae (17, 18). Normal coagulation occurs in waves with the release of storage pool constituents from platelet dense bodies controlling aggregation. Although platelet numbers are normal in CHS, platelets are defective in coagulation (19). Platelets in CHS patients contain abnormal platelet dense bodies (20, 21). These dense bodies normally contain serotonin, calcium, adenosine diphosphate (ADP), adenosine triphosphate (ATP), and pyrophosphate (22) and are responsible for the second wave of platelet aggregation. Release of storage pools requires regulated secretion and CHS platelet dense bodies appear to be delayed in secretion resulting in increased bleeding times (17).

Patients with CHS have recurrent pyogenic infections. The most common infections occur in the skin and respiratory tract (23, 24). Macrophages and particularly polymorphonuclear leukocytes (PMNs) show decreased chemotaxis (25–27). The phagocytic ability of CHS PMNs is normal, but there is a delay in fusion of phagosomes with lysosomes. This delay permits bacterial replication and escape leading to persistent infections. The current treatment for infections is antibiotics. This is, however, only a temporary solution. If patients survive the onslaught of infections they may then exhibit an `accelerated phase' lymphocyte infiltrate into the major organs of the body (23, 28). The accelerated phase is believed to be an uncontrolled T-cell activation/proliferation (23, 29). A correlation between Epstein–Barr virus infection and the onset of the accelerated phase was shown in eight CHS patients (30), suggesting that a viral insult may be responsible for the accelerated phase and corresponding T-cell proliferation. CHS patients have defective cytolytic T-cell function (31–34), impaired natural killer (NK) cell function (35), and slowed neutrophil and monocyte migration (36, 37).

The treatment for CHS is bone marrow transplant, which alleviates the immunologic problems, the most life-threatening defects of CHS (38–42). Patients who live longer then manifest neurologic defects. Typically, the neurologic symptoms include ataxia and gait problems, weakness, sensory deficits, and advancing neurodegeneration (43, 44). Microscopic examination of neurons revealed cytoplasmic inclusions resembling enlarged lysosomes, similar to that observed in all other cell types of CHS patients (45, 46). These enlarged vesicles may eventually impair synaptic transmissions.

Identification of the CHS/Beige Gene

The beige mouse has long been thought of as a homolog of CHS and this was formally demonstrated using somatic cell fusion (47). Wild type human fibroblasts were able to complement the enlarged lysosome phenotype of mouse beige fibroblasts, while CHS fibroblasts were not able to complement the beige fibroblasts nor Aleutian mink fibroblasts. These studies demonstrated that the beige/Aleutian mink mutation was in the orthologous gene to the CHS mutation. The Beige gene had been localized to chromosome 13 (48) and the CHS gene to chromosome 1q42 (49, 50). Investigators used traditional positional cloning approaches to narrow the region of the Beige gene. Two different groups simultaneously cloned the Beige gene using either a strict positional cloning strategy (7) or positional cloning combined with YAC complementation (8). The cloning of Beige and the generation of Beige cDNAs allowed for the identification of a candidate gene for CHS (7, 9). CHS1 is among the largest genes identified in the human genome with a messenger RNA (mRNA) of approximately 11.5 kb. The gene encodes a protein of 3801 amino acids with a predicted molecular weight of 430 kDa. The CHS1 and Beige protein sequences are 85% identical. Mutations in CHS1 span the entire gene with frameshift mutations identified at codons 40, 489, 633, 1026 and 3197 and non-sense mutations at codons 50, 566, and 1029 (1) as well as missense mutations (51). Together these data establish that the full-length protein is needed for function.

Several animal models of CHS have been identified, including the beige mouse (52), the beige rat (53), the Aleutian mink (23), CHS in cats (54), a reported case of CHS in killer whales (55), and Chediak in cattle (23). The bovine Chediak gene has been sequenced and a mutation identified in which a single amino acid change from an arginine to a histidine gives rise to the Chediak phenotype (56, 57). This arginine residue is conserved in CHS1 genes in other species. It is unknown if this amino acid change results in an unstable protein thus giving rise to the phenotype. This suggests that either this region of the protein is important for function or the region is required for the stability of the protein.

CHS1/Beige Protein Characterization

The CHS1 protein is predicted to be a cytosolic protein with three to four defined domains including a weak ARM/HEAT repeat domain containing alpha-helices, a possible perilipin domain, a BEACH domain (BEige And CHediak) containing the amino acid sequence WIDL and a series of WD-40 repeats at the carboxyl terminus (Fig. 2). ARM motifs are suggested to mediate membrane associations (58) and HEAT repeats are thought to play a role in vesicle transport (59, 60). The perilipin domain is suggested to be a lipid association domain (61) and is found in another vesicle trafficking protein, TIP47 (62, 63). The BEACH domain has no known function but is found in several proteins in eukaryotes (3, 64). The WD-40 repeat domain has been identified as a protein–protein interaction domain (65).


Figure 2. . A schematic representation of the CHS1/Beige protein.

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Database searches have identified a family of eukaryotic proteins that contain the BEACH and WD-40 repeat domains. There are homologs in all eukaryotes examined with several family members present in mammals, Drosophila melanogaster, Caenorhabditis elegans, Dictyostelium discoidium and one homolog in Saccharomyces cerevisiae (Fig. 3). Some of the identified CHS1 homolog have been further analyzed. Neurobeachin, a mammalian homologs, has been localized to the trans-Golgi and has been characterized as a protein kinase A anchoring protein (66). FAN, another mammalian family member, is involved in neutral sphingomyelinase activation (67). No function has been described for CDC4L (68). One of the D. melanogaster homologs, dAKAP550, has also been shown to be a protein kinase A anchoring protein (69), similar to Neurobeachin. Studies in D. discoidium have identified six BEACH/WD40 containing proteins, LvsA-F (64). Two of these proteins, LvsA and LvsB, have been further characterized. D. discoideum has a contractile vacuole complex that serves to excrete cytoplasmic water through a vesicular trafficking and insures survival in a hypo-osmotic environment. LvsA protein has been shown to be associated with the contractile vacuole of D. discoidium (70). LvsB, which has the most homology to the CHS1/Beige protein, affects vacuole morphology. The lvsB-null mutants contain enlarged acidic lysosomes, similar to Chediak or beige and the authors suggest that the LvsB protein may regulate vesicle fusion (71). Recently, a D. melanogaster homolog was disrupted and analyzed for developmental defects. A mutation in CG9011/DBEACH1 results in defects in bristle formation (72). This is the first reported information that a CHS homolog may be involved in development.


Figure 3. . A family of BEACH and WD40 containing proteins. The CHS1/Beige/LYST domain BEACH/WD40 has defined a family of genes conserved throughout evolution. Humans/mice have four family members, D. melanogaster has five members, C. elegans has three, D. discoidium has six and S. cerevisiae has one BEACH family gene.

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Somatic cell fusion experiments revealed that CHS and beige fibroblast lysosomes are capable of fusion (47). Mutant cells fused to other mutant cells by UV-Sendai virus showed lysosome mixing (fusion). Mutant cell lysosomes were capable of fusion with wild type or mutant lysosomes. No alterations in the kinetics of lysosome fusion were observed (D.M. Ward and J. Kaplan, unpublished). It is of interest to note that in fusions of CHS/beige cells with wild type cells the mutant lysosomes required fusion with wild type lysosomes in order to regain wild type morphology. These data suggest that the CHS1 protein may either associate with lysosomes at some point or alter some property of lysosomes that is essential to maintain normal lysosome size/distribution. Overexpression of the Beige protein results in smaller than normal lysosomes, suggesting a role for Beige/CHS1 in vesicle fission (73).

It was hypothesized that the cellular defect in CHS/beige might be caused by a microtubule defect (74–78). Vesicles are often transported along microtubules using retrograde and anterograde microtubule-associated motor proteins. Microtubules are normal in CHS/beige cells. Perou and Kaplan demonstrated that microtubule-associated proteins appear to function normally in CHS/beige fibroblasts (79). That is, lysosomes could move to the periphery and back to a perinuclear region in the absence of the CHS/Beige protein. These data rule out a possible defect in microtubules and microtubule-associated proteins. A previous report suggested that the CHS1/Beige protein was associated with microtubules (80). Those results have been proven incorrect (W. Faigle, personal communication), and any association of the CHS1/Beige protein with membranes or cytoskeletal elements has not been demonstrated. To date the function of the CHS1/LYST/Beige protein remains unknown.

Cellular Defects Associated with CHS

Investigators have used cell biology and biochemical techniques to try to determine the function of the CHS1/LYST/Beige protein. Some cell types have unique organelles (i.e. secretory granules, melanosomes) that perform specific functions. Because these organelles are believed to be of the same lineage as lysosomes, investigators have studied cells with these specific organelles. For example, cytotoxic T lymphocytes (CTLs) from CHS patients show abnormal secretory granules with only one to two enlarged secretory granules/lysosomes. Normally CTLs contain several small secretory granules. Baetz et al. (31) and Stinchcombe et al. (34) have shown that the CHS CTLs are unable to secrete the giant granules that contain the lytic proteins. Stinchcombe et al. (81) further demonstrated that early secretory granule biogenesis is normal in CHS. However, granule maturation is altered and CHS granules appear to fuse and generate the abnormally large granules.

Antigen presentation is dependent upon appropriate vesicular trafficking. Lem et al. (82) demonstrated that the class II loading compartment of CHS antigen-presenting cells was enlarged and that antigen processing was delayed. Faigle et al. (80) also showed a delay in antigen presentation in lymphocytes from CHS patients. These data may explain the observed defects in host defense mechanisms but they do not ascribe a function to the CHS1/LYST/Beige protein.

Changes in melanosome content, morphology, or location serve as classic identifiers of pigment disorders (83, 84) and indeed melanosomes are large and clustered near the nucleus of melanocytes in CHS. Normal pigmentation occurs by the biogenesis of melanosomes, the movement of melanosomes to the periphery of the melanocyte and release of the melanosome to the epithelium or keratinocyte. Studies have demonstrated that enlarged melanosomes in CHS/beige melanocytes contain pigments (16). Enlarged melanosomes in CHS appear to be the result of an aberrant fusion similar to observations made in CTLs (34), mast cells (85), and pancreatic acinar cells (86) where abnormal fusion of specific vesicles has been observed.

The underlying biochemical defect in CHS/beige has yet to be identified. Many studies have speculated that alteration in cyclic nucleotides (75), protein kinase C (PKC) levels (87–91), or lipid turnover/composition (91–95) may be the underlying biochemical defect. Previous studies have shown that PKC is abnormally rapidly down-regulated in beige PMNs and NK cells (89). Investigators have also shown that treating cells with inhibitors of PKC proteolysis could eliminate the rapid PKC down-regulation (90, 96). The relationship between the down-regulation of PKC and the lysosomal abnormalities in beige/CHS remains unknown. Tanabe and colleagues reported increases in ceramide production in beige fibroblasts and suggest that this results in the rapid down-regulation of PKC (91). They further showed that treatment of normal fibroblasts with a PKC inhibitor, chelerythrin, resulted in enlarged lysosomes clustered in a perinuclear region. These data suggest that in the absence of the Beige/CHS protein or when PKC levels are misregulated lysosome morphology can be altered. It is clear that the absence of the CHS/Beige protein affects the origin and/or maintenance of a specific subset of vesicles. How the CHS/Beige protein functions in this pathway remains to be determined.


  1. Top of page
  2. Abstract
  5. Acknowledgements
  6. References

Historically, CHS has provided a unique opportunity for investigators to speculate on the origin of lysosomes and lysosome-related organelles. The identification of mutations in model organisms, such as the mouse, has further advanced the understanding of this syndrome as well as other diseases that affect lysosome-related organelles. Many of these cloned mutations have helped identify genes involved in the biochemical pathways of lysosome-related organelle biogenesis and maintenance. We still know very little about the biochemical role that CHS/LYST/Beige plays in vesicular trafficking. Perhaps the identification of other BEACH family members will further our understanding of the role these proteins play in membrane trafficking.


  1. Top of page
  2. Abstract
  5. Acknowledgements
  6. References

This work is supported by the National Institute of Health grants HL26922 to J.K and a predoctoral training grant 5T32GM07464 to S.L.S.


  1. Top of page
  2. Abstract
  5. Acknowledgements
  6. References
  • 1
    Spritz RA. Genetic defects in Chediak–Higashi syndrome and the beige mouse. J Clin Immunol 1998;18: 97105
  • 2
    Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak–Higashi syndrome. Mol Genet Metab 1999;68: 283303DOI: 10.1006/mgme.1999.2927
  • 3
    Ward DM, Griffiths GM, Stinchcombe JC, Kaplan J. Analysis of the lysosomal storage disease Chediak–Higashi syndrome. Traffic 2000;1: 816822
  • 4
    Hermansky F, Pudlak P. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow; report of two cases with histochemical studies. Blood 1959;14: 162169
  • 5
    Huizing M, Anikster Y, Gahl WA. Hermansky–Pudlak syndrome and Chediak–Higashi syndrome: disorders of vesicle formation and trafficking. Thromb Haemost 2001;86: 233245
  • 6
    Pastural E, Barrat FJ, Dufourcq-Lagelouse R, Certain S, Sanal O, Jabado N, Seger R, Griscelli C, Fischer A, De Saint Basile G. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nat Genet 1997;16: 289292
  • 7
    Barbosa MD, Nguyen QA, Tchernev VT, Ashley JA, Detter JC, Blaydes SM, Brandt SJ, Chotai D, Hodgman C, Solari RC. Identification of the homologous beige and Chediak–Higashi syndrome genes. Nature 1996;382: 262265
  • 8
    Perou CM, Moore KJ, Nagle DL, Misumi DJ, Woolf EA, McGrail SH, Holmgren L, Brody TH, Dussault BJ Jr., Monroe CA. Identification of the murine beige gene by YAC complementation and positional cloning. Nat Genet 1996;13: 303308
  • 9
    Nagle DL, Karim MA, Woolf EA, Holmgren L, Bork P, Misumi DJ, McGrail SH, Dussault BJ Jr., Perou CM, Boissy RE. Identification and mutation analysis of the complete gene for Chediak–Higashi syndrome. Nat Genet 1996;14: 307311
  • 10
    Barbosa MD, Barrat FJ, Tchernev VT, Nguyen QA, Mishra VS, Colman SD, Pastural E, Dufourcq-Lagelouse R, Fischer A, Holcombe RF. Identification of mutations in two major mRNA isoforms of the Chediak–Higashi syndrome gene in human and mouse. Hum Mol Genet 1997;6: 10911098
  • 11
    Karim MA, Nagle DL, Kandil HH, Burger J, Moore KJ, Spritz RA. Mutations in the Chediak–Higashi syndrome gene (CHS1) indicate requirement for the complete 3801 amino acid CHS protein. Hum Mol Genet 1997;6: 10871089
  • 12
    Windhorst DB, Zelickson AS, Good RA. A human pigmentary dilution based on a heritable subcellular structural defect – the Chediak–Higashi syndrome. J Invest Dermatol 1968;50: 918
  • 13
    BenEzra D, Mengistu F, Cividalli G, Weizman Z, Merin S, Auerbach E. Chediak–Higashi syndrome: ocular findings. J Pediatr Ophthalmol Strabismus 1980;17: 6874
  • 14
    Valenzuela R, Morningstar WA. 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;75: 591596
  • 15
    Spencer WH, Hogan MJ. Ocular manifestations of Chediak–Higashi syndrome: Report of a case with histopathologic examination of ocular tissues. Am J Ophthalmol 1960;50: 11971203
  • 16
    Zhao H, Boissy YL, Abdel-Malek Z, King RA, Nordlund JJ, Boissy RE. On the analysis of the pathophysiology of Chediak–Higashi syndrome. Defects expressed by cultured melanocytes. Laboratory Invest 1994;71: 2534
  • 17
    Buchanan GR, Handin RI. Platelet function in the Chediak–Higashi syndrome. Blood 1976;47: 941948
  • 18
    Rendu F, Breton-Gorius J, Lebret M, Klebanoff C, Buriot D, Griscelli C, Levy-Toledano S, Caen JP. Evidence that abnormal platelet functions in human Chediak–Higashi syndrome are the result of a lack of dense bodies. Am J Pathol 1983;111: 307314
  • 19
    Apitz-Castro R, Cruz MR, Ledezma E, Merino F, Ramirez-Duque P, Dangelmeier C, Holmsen H. The storage pool deficiency in platelets from humans with the Chediak–Higashi syndrome: study of six patients. Br J Haematol 1985;59: 471483
  • 20
    Parmley RT, Rahemtulla F, Cooper MD, Roden L. Ultrastructural and biochemical characterization of glycosaminoglycans in HNK-1-positive large granular lymphocytes. Blood 1985;66: 2025
  • 21
    White JG. Platelet microtubules and giant granules in the Chediak–Higashi syndrome. Am J Med Technol 1978;44: 273278
  • 22
    Holmsen H, Weiss HJ. Secretable storage pools in platelets. Ann Rev Med 1979;30: 119134
  • 23
    Padgett GA, Reiquam CW, Gorham JR, Henson JB, O'Mary CC. Comparative studies of the Chediak–Higashi syndrome. Am J Pathol 1967;51: 553571
  • 24
    Blume RS, Wolff SM. The Chediak–Higashi syndrome: studies in four patients and a review of the literature. Medicine (Baltimore) 1972;51: 247280
  • 25
    Baehner RL. Molecular basis for functional disorders of phagocytes. J Pediatr 1974;84: 317327
  • 26
    Lynch MJ. Mechanisms and defects of the phagocytic systems of defense against infection. Perspect Pediatr Pathol 1973;1: 33115
  • 27
    Quie PG. Disorders of phagocyte function. Curr Probl Pediatr 1972;2: 353
  • 28
    Singh RP, Gupta P, Santendra, Sen B. Chediak–Higashi syndrome – accelerated phase. Indian Pediatr 1994;31: 445448
  • 29
    Rubin CM, Burke BA, McKenna RW, McClain KL, White JG, Nesbit ME Jr., Filipovich AH. The accelerated phase of Chediak–Higashi syndrome. An expression of the virus-associated hemophagocytic syndrome? Cancer 1985;56: 524530
  • 30
    Certain S, Barrat F, Pastural E, Le Deist F, Goyo-Rivas J, Jabado N, Benkerrou M, Seger R, Vilmer E, Beullier G. Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak–Higashi syndrome. Blood 2000;95: 979983
  • 31
    Baetz K, Isaaz S, Griffiths GM. Loss of cytotoxic T lymphocyte function in Chediak–Higashi syndrome arises from a secretory defect that prevents lytic granule exocytosis. J Immunol 1995;154: 61226131
  • 32
    Barrat FJ, Le Deist F, Benkerrou M, Bousso P, Feldmann J, Fischer A, De Saint Basile G. Defective CTLA-4 cycling pathway in Chediak–Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation. Proc Natl Acad Sci USA 1999;96: 86458650
  • 33
    Stinchcombe JC, Griffiths GM. Regulated secretion from hemopoietic cells. J Cell Biol 1999;147: 16
  • 34
    Stinchcombe JC, Page LJ, Griffiths GM. Secretory lysosome biogenesis in cytotoxic T lymphocytes from normal and Chediak–Higashi syndrome patients. Traffic 2000;1: 435444DOI: 10.1034/j.1600-0854.2000.010508.x
  • 35
    Abo T, Roder JC, Abo W, Cooper MD, Balch CM. Natural killer (HNK-1+) cells in Chediak–Higashi patients are present in normal numbers but are abnormal in function and morphology. J Clin Invest 1982;70: 193197
  • 36
    Haliotis T, Roder J, Klein M, Ortaldo J, Fauci AS, Herberman RB. Chediak–Higashi gene in humans I. Impairment of natural-killer function. J Exp Med 1980;151: 10391048
  • 37
    Klein M, Roder J, Haliotis T, Korec S, Jett JR, Herberman RB, Katz P, Fauci AS. Chediak–Higashi gene in humans. II. The selectivity of the defect in natural-killer and antibody-dependent cell-mediated cytotoxicity function. J Exp Med 1980;151: 10491058
  • 38
    Haddad E, Le Deist F, Blanche S, Benkerrou M, Rohrlich P, Vilmer E, Griscelli C, Fischer A. Treatment of Chediak–Higashi syndrome by allogenic bone marrow transplantation: report of 10 cases. Blood 1995;85: 33283333
  • 39
    Kazmierowski JA, Elin RJ, Reynolds HY, Durbin WA, Wolff SM. Chediak–Higashi syndrome: reversal of increased susceptibility to infection by bone marrow transplantation. Blood 1976;47: 555559
  • 40
    Virelizier JL, Lagrue A, Durandy A, Arenzana F, Oury C, Griscelli C, Reinert P. Reversal of natural killer defect in a patient with Chediak–Higashi syndrome after bone-marrow transplantation. N Engl J Med 1982;306: 10551056
  • 41
    Mottonen M, Lanning M, Saarinen UM. Allogeneic bone marrow transplantation in Chediak–Higashi syndrome. Pediatr Hematol Oncol 1995;12: 5559
  • 42
    Liang JS, Lu MY, Tsai MJ, Lin DT, Lin KH. Bone marrow transplantation from an HLA-matched unrelated donor for treatment of Chediak–Higashi syndrome. J Formos Med Assoc 2000;99: 499502
  • 43
    Sung JH, Stadlan EM. Neuropathological changes in Chediak–Higashi disease. J Neuropathol Exp Neurol 1968;27: 156157
  • 44
    Sung JH, Meyers JP, Stadlan EM, Cowen D, Wolf A. Neuropathological changes in Chediak–Higashi disease. J Neuropathol Exp Neurol 1969;28: 86118
  • 45
    Hirano A, Zimmerman HM, Levine S, Padgett GA. Cytoplasmic inclusions in Chediak–Higashi and Wobbler mink. An electron microscopic study of the nervous system. J Neuropathol Exp Neurol 1971;30: 470487
  • 46
    Libert J, Dhermy P, Van Hoof F, Dufier JL, Cornu G. Ocular findings in Chediak–Higashi disease: a light and electron microscopic study of two patients. Birth Defects Orig Artic Series 1982;18: 327344
  • 47
    Perou CM, Kaplan J. Complementation analysis of Chediak–Higashi syndrome: the same gene may be responsible for the defect in all patients and species. Somat Cell Mol Genet 1993;19: 459468
  • 48
    Justice MJ, Silan CM, Ceci JD, Buchberg AM, Copeland NG, Jenkins NA. A molecular genetic linkage map of mouse chromosome 13 anchored by the beige (bg) and satin (sa) loci. Genomics 1990;6: 341351
  • 49
    Barrat FJ, Auloge L, Pastural E, Lagelouse RD, Vilmer E, Cant AJ, Weissenbach J, Le Paslier D, Fischer A, De Saint Basile G. Genetic and physical mapping of the Chediak–Higashi syndrome on chromosome 1q42–43. Am J Hum Genet 1996;59: 625632
  • 50
    Fukai K, Oh J, Karim MA, Moore KJ, Kandil HH, Ito H, Burger J, Spritz RA. Homozygosity mapping of the gene for Chediak–Higashi syndrome to chromosome 1q42–q44 in a segment of conserved synteny that includes the mouse beige locus (bg). Am J Hum Genet 1996;59: 620624
  • 51
    Karim MA, Suzuki K, Fukai K, Oh J, Nagle DL, Moore KJ, Barbosa E, Falik-Borenstein T, Filipovich A, Ishida Y. Apparent genotype–phenotype correlation in childhood, adolescent, and adult Chediak–Higashi syndrome. Am J Med Genet 2002;108: 1622
  • 52
    Lutzner MA, Lowrie CT, Jordan HW. Giant granules in leukocytes of the beige mouse. J Hered 1967;58: 299300
  • 53
    Nishimura M, Inoue M, Nakano T, Nishikawa T, Miyamoto M, Kobayashi T, Kitamura Y. Beige rat: a new animal model of Chediak–Higashi syndrome. Blood 1989;74: 270273
  • 54
    Kramer JW, Davis WC, Prieur DJ. The Chediak–Higashi syndrome of cats. Laboratory Invest 1977;36: 554562
  • 55
    Ridgway SH. Reported causes of death of captive killer whales (Orcinus orca). J Wildl Dis 1979;15: 99104
  • 56
    Yamakuchi H, Agaba M, Hirano T, Hara K, Todoroki J, Mizoshita K, Kubota C, Tabara N, Sugimoto Y. Chediak–Higashi syndrome mutation and genetic testing in Japanese black cattle (Wagyu). Anim Genet 2000;31: 1319DOI: 10.1046/j.1365-2052.2000.00586.x
  • 57
    Kunieda T, Nakagiri M, Takami M, Ide H, Ogawa H. Cloning of bovine LYST gene and identification of a missense mutation associated with Chediak–Higashi syndrome of cattle. Mamm Genome 1999;10: 11461149
  • 58
    Peifer M, Berg S, Reynolds AB. A repeating amino acid motif shared by proteins with diverse cellular roles [letter]. Cell 1994;76: 789791
  • 59
    Andrade MA, Petosa C, O'Donoghue SI, Muller CW, Bork P. Comparison of ARM and HEAT protein repeats. J Mol Biol 2001;309: 118DOI: 10.1006/jmbi.2001.4624
  • 60
    Andrade MA, Bork P. HEAT repeats in the Huntington's disease protein. Nat Genet 1995;11: 115116
  • 61
    Londos C, Brasaemle DL, Schultz CJ, Segrest JP, Kimmel AR. Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells. Semin Cell Dev Biol 1999;10: 5158
  • 62
    Diaz E, Pfeffer SR. TIP47: a cargo selection device for mannose 6-phosphate receptor trafficking. Cell 1998;93: 433443
  • 63
    Krise JP, Sincock PM, Orsel JG, Pfeffer SR. Quantitative analysis of TIP47-receptor cytoplasmic domain interactions: implications for endosome-to-trans Golgi network trafficking. J Biol Chem 2000;275:25 18825 193
  • 64
    Cornillon S, Dubois A, Bruckert F, Lefkir Y, Marchetti A, Benghezal M, De Lozanne A, Letourneur F, Cosson P. Two members of the beige/CHS (BEACH) family are involved at different stages in the organization of the endocytic pathway in Dictyostelium. J Cell Sci 2002;115: 737744
  • 65
    Neer EJ, Schmidt CJ, Nambudripad R, Smith TF. The ancient regulatory-protein family of WD-repeat proteins. Nature 1994;371: 297300
  • 66
    Wang X, Herberg FW, Laue MM, Wullner C, Hu B, Petrasch-Parwez E, Kilimann MW. Neurobeachin: a protein kinase A-anchoring, beige/Chediak-higashi protein homolog implicated in neuronal membrane traffic. J Neurosci 2000;20: 85518565
  • 67
    Adam-Klages S, Adam D, Wiegmann K, Struve S, Kolanus W, Schneider-Mergener J, Kronke M. FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase. Cell 1996;86: 937947
  • 68
    Feuchter AE, Freeman JD, Mager DL. Strategy for detecting cellular transcripts promoted by human endogenous long terminal repeats: identification of a novel gene (CDC4L) with homology to yeast CDC4. Genomics 1992;13: 12371246
  • 69
    Han JD, Baker NE, Rubin CS. Molecular characterization of a novel A kinase anchor protein from Drosophila melanogaster. J Biol Chem 1997;272: 2661126619
  • 70
    Gerald NJ, Siano M, De Lozanne A. The dictyostelium LvsA protein is localized on the contractile vacuole and is required for osmoregulation. Traffic 2002;3: 5060DOI: 10.1034/j.1600-0854.2002.30107.x
  • 71
    Harris E, Wang N, Wu Wl WL, Weatherford A, De Lozanne A, Cardelli J. Dictyostelium LvsB mutants model the lysosomal defects associated with Chediak–Higashi syndrome. Mol Biol Cell 2002;13: 656669
  • 72
    Kraut R, Menon K, Zinn K. A gain-of-function screen for genes controlling motor axon guidance and synaptogenesis in Drosophila. Curr Biol 2001;11: 41744130
  • 73
    Perou CM, Leslie JD, Green W, Li L, Ward DM, Kaplan J. The Beige/Chediak–Higashi syndrome gene encodes a widely expressed cytosolic protein. J Biol Chem 1997;272:29 79029 794
  • 74
    Oliver JM, Zurier RB. Correction of characteristic abnormalities of microtubule function and granule morphology in Chediak–Higashi syndrome with cholinergic agonists. J Clin Invest 1976;57: 12391247
  • 75
    Oliver JM. Impaired microtubule function correctable by cyclic GMP and cholinergic agonists in the Chediak–Higashi syndrome. Am J Pathol 1976;85: 395418
  • 76
    Hinds K, Danes BS. Letter: Microtubular defect in Chediak–Higashi syndrome. Lancet 1976;2: 146147
  • 77
    Boxer LA, Watanabe AM, Rister M, Besch HR Jr., Allen J, Baehner RL. Correction of leukocyte function in Chediak–Higashi syndrome by ascorbate. N Engl J Med 1976;295: 10411045
  • 78
    Boxer LA, Albertini DF, Baehner RL, Oliver JM. Impaired microtubule assembly and polymorphonuclear leucocyte function in the Chediak–Higashi syndrome correctable by ascorbic acid. Br J Haematol 1979;43: 207213
  • 79
    Perou CM, Kaplan J. Chediak–Higashi syndrome is not due to a defect in microtubule-based lysosomal mobility. J Cell Sci 1993;106: 99107
  • 80
    Faigle W, Raposo G, Tenza D, Pinet V, Vogt AB, Kropshofer H, Fischer A, De Saint-Basile G, Amigorena S. Deficient peptide loading and MHC class II endosomal sorting in a human genetic immunodeficiency disease: the Chediak–Higashi syndrome. J Cell Biol 1998;141: 11211134
  • 81
    Stinchcombe JC, Griffiths GM. Normal and abnormal secretion by haemopoietic cells. Immunology 2001;103: 1016DOI: 10.1046/j.1365-2567.2001.01225.x
  • 82
    Lem L, Riethof DA, Scidmore-Carlson M, Griffiths GM, Hackstadt T, Brodsky FM. Enhanced interaction of HLA-DM with HLA-DR in enlarged vacuoles of hereditary and infectious lysosomal diseases. J Immunol 1999;162: 523532
  • 83
    Marks MS, Seabra MC. The melanosome: membrane dynamics in black and white. Nat Rev Mol Cell Biol 2001;2: 738748
  • 84
    Lloyd V, Ramaswami M, Kramer H. Not just pretty eyes: Drosophila eye-colour mutations and lysosomal delivery. Trends Cell Biol 1998;8: 257259
  • 85
    Galli SJ, Dvorak AM, Hammel I. Mast cell abnormalities in the Chediak–Higashi syndrome. Int Arch Allergy Immunol 1993;100: 8992
  • 86
    Hammel I, Dvorak AM, Fox P, Shimoni E, Galli SJ. Defective cytoplasmic granule formation. II. Differences in patterns of radiolabeling of secretory granules in beige versus normal mouse pancreatic acinar cells after [3H]glycine administration in vivo. Cell Tissue Res 1998;293: 445452
  • 87
    Boxer LA, Smolen JE. Neutrophil granule constituents and their release in health and disease. Hematol Oncol Clin North Am 1988;2: 101134
  • 88
    Cui SH, Tanabe F, Terunuma H, Iwatani Y, Nunoi H, Agematsu K, Komiyama A, Nomura A, Hara T, Onodera T. A thiol proteinase inhibitor, E-64-d, corrects the abnormalities in concanavalin A cap formation and the lysosomal enzyme activity in leucocytes from patients with Chediak–Higashi syndrome by reversing the down-regulated protein kinase C activity. Clin Exp Immunol 2001;125: 283290
  • 89
    Ito M, Tanabe F, Takami Y, Sato A, Shigeta S. Rapid down-regulation of protein kinase C in (Chediak–Higashi syndrome) beige mouse by phorbol ester. Biochem Biophys Res Commun 1988;153: 648656
  • 90
    Ito M, Sato A, Tanabe F, Ishida E, Takami Y, Shigeta S. The thiol proteinase inhibitors improve the abnormal rapid down-regulation of protein kinase C and the impaired natural killer cell activity in (Chediak–Higashi syndrome) beige mouse. Biochem Biophys Res Commun 1989;160: 433440
  • 91
    Tanabe F, Cui SH, Ito M. Abnormal down-regulation of PKC is responsible for giant granule formation in fibroblasts from CHS (beige) mice – a thiol proteinase inhibitor, E-64-d, prevents giant granule formation in beige fibroblasts. J Leukoc Biol 2000;67: 749755
  • 92
    Kanfer JN, Richards R, Kampine JP, Handmaker S, Yankee RA. Alteration of e sphingolipid content in leucocytes from patients with Chediak–Higashi syndrome. Life Sci 1967;6: 26612664
  • 93
    Kanfer JN, Blume RS, Yankee RA, Wolff SM. Alteration of sphingolipid metabolism in leukocytes from patients with the Chediak–Higashi syndrome. N Engl J Med 1968;279: 410413
  • 94
    Prueitt JL, Chi EY, Lagunoff D. Pulmonary surface-active materials in the Chediak–Higashi syndrome. J Lipid Res 1978;19: 410415
  • 95
    Ingraham LM, Burns CP, Boxer LA, Baehner RL, Haak RA. Fluidity properties and liquid composition of erythrocyte membranes in Chediak–Higashi syndrome. J Cell Biol 1981;89: 510516
  • 96
    Sato A, Tanabe F, Ito M, Ishida E, Shigeta S. Thiol proteinase inhibitors reverse the increased protein kinase C down-regulation and concanavalin A cap formation in polymorphonuclear leukocytes from Chediak–Higashi syndrome (beige) mouse. J Leukoc Biol 1990;48: 377381