Chediak-Higashi syndrome

Jerry Kaplan, Ivana De Domenico and Diane McVey Ward

Department of Pathology, University of Utah School of
Medicine, Salt Lake City, Utah, USA
Correspondence to Diane McVey Ward, Department of
Pathology, University of Utah School of Medicine,
30 N. 1900 E. Salt Lake City, UT 84132, USA
Tel: +1 801 581 4967; fax: +1 801 581 6001;
e-mail: diane.mcveyward@path.utah.edu
Current Opinion in Hematology 2008, 15:22–29
Purpose of review
Chediak-Higashi syndrome, a rare autosomal recessive disorder, was described over
50 years ago. Patients show hypopigmentation, recurrent infections, mild coagulation
defects and varying neurologic problems. Treatment is bone marrow transplant, which is
effective in treating the hematologic and immune defects, however the neurologic
problems persist. The CHS1/LYST gene was identified over 10 years ago and
homologous CHS1/LYST genes are present in all eukaryotes. This review will discuss
the advances made in understanding the clinical aspects of the syndrome and the
function of CHS1/LYST/Beige.
Recent findings
Clinical reports of Chediak-Higashi syndrome have identified mutations throughout the
CHS1/LYST gene. The nature of the mutation can be a predictor of the severity of the
disease. Over the past decade the CHS1/LYST family of proteins has been analyzed
using model organisms, two-hybrid analysis, overexpression phenotypes and dominant
negatives. These studies suggest that the CHS1/LYST protein is involved in either
vesicle fusion or fission.
Summary
Although CHS is a rare disease, the Chediak-like family of proteins is providing insight
into the regulation of vesicle trafficking. Understanding the basic mechanisms that
govern vesicle trafficking will provide essential information regarding how loss of CHS1/
LYST affects hematologic, immunologic and neurologic processes.

Keywords
Beige and Chediak domain, beige mouse, lysosome, melanosome, secretory granule,
vesicle trafficking

Curr Opin Hematol 15:22–29

ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1065-6251

described as beige. Morphologic examination of vesicles

Introduction in beigej mouse cells revealed enlarged lysosome-related
Chediak-Higashi syndrome (CHS) is a rare, autosomal
organelles clustered in a perinuclear region (Fig. 1b). The
recessive disorder characterized by severe immunodefi-
gene responsible for beigej was cloned in 1996 [9,10]
ciency, bleeding tendency, frequent bacterial infections,
followed by the cloning of the mutant gene responsible
variable albinism, and progressive neurologic dysfunction.
for CHS [9,11]. The human gene is referred to as CHS1/
It is also associated with a lymphoproliferative disorder
LYST and the murine homologue is called Beige. CHS/
termed the ‘accelerated phase’, which is characterized by a
Beige genes are highly conserved in sequence and the
lymphocytic infiltration of the major organs of the body
mouse gene can correct the large lysosome phenotype of
[1–5]. A classic diagnostic feature of the disease is enlarged
CHS cells. The function of the CHS/LYST protein
vesicles in all cell types [6,7] (Fig. 1a). The enlarged
remains to be determined. Here we describe the pheno-
vesicles are of lysosome origin and include lysosomes,
types associated with CHS mutations, the identification
melanosomes, platelet dense granules and cytolytic gran-
of the Beige and Chediak (BEACH) family of proteins
ules. The occurrence of this disorder is rare and fewer than
and the proposed cellular defects associated with
500 cases have been reported in the past 15–20 years.
mutations in CHS1/Beige.
Treatment for this disorder is prophylactic antibiotics to
cure opportunistic pathogens followed by bone marrow
transplant; however, patients with bone marrow transplant Clinical manifestations
often progress to display the neurologic defects associated CHS is a lethal disorder that can be characterized by
with this disorder. diverse clinical manifestations. Patients are initially diag-
nosed based upon partial albinism and recurrent pyogenic
A mouse model of CHS was identified several decades infections. CHS patients show varying degrees of altered
ago [8]. The mouse showed a coat-color alteration pigmentation [12]. Hair color may range from grey to
1065-6251 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

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 Chediak-Higashi syndrome Kaplan et al. 23

Figure 1 Lysosome morphology in Chediak-Higashi syndrome (CHS) and beigej fibroblasts

(a) Human fibroblasts from control and

CHS patients were fixed in formaldehyde
and Lamp-1 (a lysosomal marker) localized
by immunofluorescent microscopy using a
mouse anti-Lamp-1 antibody from
Developmental Hybridoma (University of
Iowa) followed by an Alexa 488 conjugated
goat antimouse immunoglobulin G. (b)
Mouse C57/B6 or beigej fibroblasts were
processed as in (a) using a rat anti-Lamp-1
antibody followed by an Alexa 488
conjugated goat antirabbit IgG. Images
were captured on an Olympus BX51
epifluorescent microscope (60X oil/1.3
aperature) using Picture framer software.
WT, wild type.

white depending upon the ethnic background of the
patient [13]. Frequently, patients show alterations in
eye pigmentation as well, with resulting photosensitivity
and decreased visual acuity [14,15]. Patients with CHS
have recurrent bacterial infections, especially in the
respiratory tract and skin where opportunistic pathogens
frequently reside [16,17]. Patients with CHS show mild
coagulation defects often manifesting as bruising and
mucosal bleeding as a result of defective platelets [18–
22]. Mutations in CHS1/LYST also give rise to neurologic
problems, including weakness, ataxia, sensory deficits
and progressive neurodegeneration [23–27].
CHS patients that do not succumb early to bacterial
infections subsequently develop a lymphohistocytic infil-
tration into the major organs of the body. This lymphocyte
and macrophage infiltration is described as the ‘accelerated
phase’ and the exact cause of this infiltration and prolifer-
ation is unclear [28–30]. Studies have suggested that the
accelerated phase is due to uncontrolled T-cell and macro-
phage activation in response to a viral infection or defective
T-cell function [31–34]. Patients usually succumb to the
accelerated phase due to organ failure. Interestingly,
animal models of CHS (beigej mouse, Aleutian mink) do
not show the accelerated phase.
Treatment
Patients with CHS are treated prophylactically with
antibiotics. This is effective in controlling recurrent
infections but does not prevent the other complications
of CHS, including bleeding, onset of the accelerated
phase or neurologic problems. Over the past 15 years
allogeneic hematopoietic cell transplantation (HCT) has
been utilized for successful treatment of the hematologic
and immunologic complications of CHS [35–40].
Recently, Eapen and collegues [41

] reviewed out-
comes of 35 patients who received transplantation.
They noted that if CHS patients exhibited the ‘accel-
erated phase’ of the disease at the time of transplant
they had a higher rate of mortality. No assessment of
neurological outcomes was reported but it is not
expected that bone marrow transplantation would
prevent neurological deficits.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 24 Myeloid biology
Cellular defect
The altered lysosome/granule size associated with CHS
has been used as a hallmark to describe the subcellular
morphologic defect associated with the disease. All cells
of the body show abnormally enlarged lysosomes or
lysosome-related organelles. CHS/beigej melanocytes con-
tain pigment granules (melanosomes) that are enlarged
and do not get distributed appropriately to keratinocytes
or epithelial cells [7,42]. It has been suggested that the
enlarged melanosomes are the result of aberrant fusion.
Similarly, the defects in resistance to bacterial infections
and the neurologic defects can be ascribed to enlarged
vesicles failing to be ‘moved’ to the appropriate site of
action. A recent finding suggests that plasma membrane
repair may also be defective in patients with CHS,
possibly exacerbating the severe symptoms of CHS
[43]. Plasma membrane repair is a calcium-dependent
vesicle-mediated process in which peripheral small lyso-
somes fuse with the plasma membrane, resealing the
wound [44]. In CHS and beigej mouse fibroblasts plasma
membrane resealing is impaired. This impairment has
been attributed to the fact that CHS/beigej lysosomes are
enlarged, limiting their ability to traffic to and fuse with
the plasma membrane.
Analysis of cytotoxic T lymphocytes suggested that the
early stages of granule formation are normal in CHS [45].
The enlarged granule defect associated with CHS is seen
as the secretory granules mature [46]. The enlarged
cytolytic granules are postulated to form as a result of
aberrant granule fusion [47]. CHS/beigej neutrophils show
enlarged azurophilic granules but not enlarged gelatinase
or specific granules [48]. It is not understood why only
azurophilic granules are affected.
The CHS1/LYST protein regulates lysosome-related
organelle size and movement, although its role is unde-
fined. Microtubules are normal in CHS/beigej. One study
demonstrated that the CHS1/LYST protein was associated
with microtubules by examining immunolocalization of
the Beige protein to microtubules in HeLa cells using
rabbit anti-Beige antibodies. A similar staining pattern
was observed, however, in mouse and human fibro-
blasts with mutations in the CHS1/LYST/Bg gene,
suggesting that the staining is not specific for CHS1/
LYST/Beige but may reflect nonspecific staining of
microtubules with the polyclonal antibody (D. Ward,
unpublished data).
The underlying biochemical defect in CHS/beigej has not
been determined. Studies have suggested that alterations
in protein kinase C (PKC) levels in CHS give rise to
enlarged lysosome-related organelles [49]. Protein kinase
C levels are low in beigej cells. Treatment of cells with
inhibitors of PKC proteolysis increased PKC levels and
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
reduced the enlarged vesicle size associated with CHS/
beigej [50,51]. Further, inhibition of PKC activity in wild
type cells resulted in enlarged perinuclear lysosomes, and
oral administration of PKC proteolysis inhibitors (E-64-d)
to beigej mice resulted in improved lysosomal enzyme
activity and improved bactericidal activity [52

]. This
treatment also resulted in a significant increase in survival
rate of beigej mice infected with Staphylococcus aureus. The
authors proposed that treatment with PKC inhibitors may
be effective in bacterial infections in CHS. It remains
unclear, however, if alteration in PKC levels is the
immediate biochemical defect resulting from loss of
CHS1/LYST/Beige or if changes in PKC levels are a
more downstream effect.
Analysis of the BEACH family of proteins
The sequence of CHS1/LYST/Beige was relatively
unrevealing, as there are few motifs with assigned func-
tions [10,11]. CHS1/LYST is predicted to be a 430 kDa
cytosolic protein with several ARM/HEAT a-helix repeats
in the amino terminus that may mediate membrane
interactions (Fig. 2). HEAT repeats are 40–50 amino
acid segments containing conserved residues (proline11,
aspartic acid19 and arginine25) with several flanking
hydrophobic residues [53–55]. The extreme carboxyl ter-
minus consists of a set of WD-40 (tryptophan-aspartic acid)
repeats. The WD-40 domain is a well established protein
interaction domain [56]. Adjacent to the WD-40 domain is
a sequence that is enriched in the amino acids WIDL
(tryptophan, isoleucine, aspartic acid, leucine). This
domain has been termed the BEACH motif. The WIDL
sequence along with the WD-40 repeat motifs define a
family of proteins that are homologous to CHS1/LYST/
Beige [3,4,57].
Figure 2 Chediak-Higashi syndrome (CHS)/LYST/Beige protein
domains
CHS1/LYST/Beige
BEACH
ARM/HEAT repeat WIDL WD repeats
1 3801 aa
Perilipin domain
(1079--1313)
The CHS/LYST/Beige gene encodes a protein of approximately 3800
amino acids (aa). The amino acid sequence shows four defined domains.
The amino terminus contains up to 20 HEAT/ARM repeat domains that are
predicted to mediate membrane interactions. The protein also contains a
predicted perilipin domain at position 1079–1313. There is a conserved
amino acid sequence tryptophan, isoleucine, aspartic acid and leucine
(WIDL) at approximately 2850 of unknown function. In the carboxyl
terminus there are seven repeat domains containing the conserved amino
acids tryptophan (W) and aspartic acid (D) that are predicted to be protein
interactions domains. Together the WIDL and WD repeat domains define
a family of proteins called Beige and Chediak (BEACH).
 Chediak-Higashi syndrome Kaplan et al. 25

The cloning of the Beige and CHS1/LYST genes and
sequencing of mutant genes has determined that missense
and nonsense mutations occur throughout the CHS1/
LYST/Beige gene [9,11,58–63]. It has been proposed that
the nature of the mutations may predict disease severity. In
general, patients with missense mutations show less
severe clinical phenotypes compared with patients with
nonsense mutations. Corroboration of this idea comes from
a mouse model of CHS that was generated using ENU
mutagenesis [62]. Sequence analysis identified a novel
missense mutation in the carboxyl terminus of the
Beige gene at amino acid position 3681. The resulting
phenotype associated with this mutation was not the
classic immunologic defect but manifested only as a
late-onset neurologic disorder. This and other observations
suggest that some patients with missense mutations may
make a partially functional CHS1/LYST protein. Formal
proof of this hypothesis would be to measure protein
levels; however, endogenous CHS/LYST/Beige protein
levels are extremely difficult to detect.
The annotation of the sequence along with the ‘genome
sequencing explosion’ has shown that CHS1/LYST/Beige
is a highly conserved gene with homologues in all
eukaryotes. The BEACH motif has defined a family of
proteins with several organisms containing more than one
BEACH family member (Table 1). Mammals and
Dictyostelium contain six or more BEACH members,
Drosophila and Arabidopsis have five BEACH proteins,
Caenorhabditis has three family members and Schizosac-
charomyces and Saccharomyces each have one homologue.
The identification of these homologues has allowed for
further analysis of the biochemical roles of the BEACH
family of proteins. The smallest mammalian WD-40
protein FAN has been shown to bind the tumor necrosis
factor receptor and activate neutral sphingomyelinase
[64–66]. To understand how FAN activates neutral
sphingomyelinase a FAN-deficient mouse strain was
generated. FAN-deficient mice show no marked pheno-
typic abnormalities but do show a delay in cutaneous
wound repair. Recently, it has been reported that
FAN-deficient mouse cells have slightly enlarged lyso-
somes, a phenotype primarily associated with CHS/beigej
[67]. The defect in wound repair seen in FAN-deficient
mice is similar to the reports of defective wound repair in
CHS/beigej [43].
The BEACH family member neurobeachin, which is
strongly expressed in neural tissues, has been character-
ized as a protein kinase A (PKA) binding protein with a
role in evoked vesicle release at the neuromuscular
junction [68,69]. Neurobeachin has also been implicated
as a candidate gene for autism [70]. LRBA, previously
referred to as CDC4L, is ubiquitously expressed and is
also a PKA anchoring protein proposed to function in
polarized vesicle trafficking [71]. Increased expression of
LRBA has been observed to increase cancer growth [72].

Table 1 The Beige and Chediak (BEACH) family of proteins

Organism Gene/protein Function

Mammals CHS1/LYST/Beige Regulates lysosome-related organelle size

FAN Binds tumor necrosis factor receptor activating N-sphingomyelinase
Neurobeachin Protein kinase A anchoring protein involved in vesicular release at the
neuromuscular junction
LRBA/CDC4L Protein kinase A anchoring protein involved in vesicular release in polarized cells
ALFY Phosphoinositol-3-phosphate binding protein
Drosophilia melanogaster AKAP550/CG18799.1 Protein kinase A anchoring protein involved in vesicular release in polarized cells
BCHS (blue cheese)/CG14001 Antagonist of Rab 11
CG1332 Unknown
CG6734 Unknown
CG9001 Unknown
CG11814 Unknown
Caenorhabditis elegans SEL-2 F10F2.1 Protein kinase A anchoring protein involved in vesicular release in
polarized cells
VT23B5.2
T01H10.8
Arabidopsis thaliana T18124.16 Unknown
F16M22.8 Unknown
At2g45540 Unknown
F1003.12 Unknown
T10P11.5 Unknown
Dictyostelium discoideum LvsA Involved in cytokinesis and osmoregulation
LvsB Negative regulator of lysosome fusion/involved in the biogenesis of
post lysosomes
LvsC Unknown
LvsD Unknown
LvsE Unknown
LvsF Unknown
Saccharomyces cerevisiae Bph1 Protein sorting and cell wall formation

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 26 Myeloid biology
Mutations in the Drosophila LRBA homologue
DAKAP550 give rise to defects in eye development con-
sistent with alterations in Notch and epidermal growth
factor receptor (EGFR) signaling [73
]. The C. elegans
homologue SEL-2, which is most homologous to LRBA
and neurobeachin, is also involved in endosomal traffick-
ing in polarized epithelial cells [74
]. SEL-2 appears to be a
negative regulator of Notch/lin-12 activity and mutations
in SEL-2 result in basolateral mislocalization and accumu-
lation of Notch/lin-12 activity (EGFR activity).
ALFY is a ubiquitously expressed BEACH protein that
contains a FYVE zinc-finger domain at the end of the
WD-40 repeats [75]. The FYVE domain mediates binding
to phosphatidylinositol-3-phosphate, a phosphatidylinosi-
tol phosphate that regulates endocytic and autophagic
membrane trafficking. The Drosophila ALFY homologue
blue cheese (bchs) has been shown to be an antagonist of Rab
11, a GTPase involved in membrane trafficking
[73
,76
,77]. Khodosh et al. [73
] extended their findings,
uncovering a role for bchs in synaptic morphogenesis and
postulating that BEACH proteins may act through
Rab proteins.
Structural analyses of the BEACH domain of neurobea-
chin and LRBA have revealed a weakly conserved pleck-
strin homology domain upstream of the BEACH domain in
members of the BEACH family [78,79]. Pleckstrin
homology domains can function in phospholipid binding
or protein–protein interactions [80]. The structural
analyses suggest that the pleckstrin homology domain in
BEACH proteins acts as a protein–protein interaction
domain. Gebauer et al. [79] have determined that the
pleckstrin homology domain of these proteins interacts
with the BEACH domain and may mediate intramolecular
folding.
Dictyostelium has six BEACH proteins [57]. Two of those
proteins have been characterized [81]. Studies have
identified a role for LvsA in cytokinesis and osmoregula-
tion [82,83]. LvsB, which is most similar to CHS/LYST/
Beige, is localized on lysosomes and an organelle called
the postlysosome [84
]. lvsB-null Dictyostelium show
enlarged vesicles and kinetic studies suggest that LvsB
may be a negative regulator of lysosome fusion [85].
Saccharomyces cerevisiae has one CHS1/LYST/Beige hom-
ologue, Bph1, and this protein is involved in protein sorting
and cell wall formation, but deletion of the gene BPH1 did
not give rise to an enlarged vacuole/lysosome [86]. Protein
sorting and cell wall formation are dependent on appro-
priate vesicular trafficking and the phenotype associated
with loss of Bph1 suggests that this BEACH homologue is
also involved in vesicular trafficking. In summary, all
BEACH family members have been described to be
involved in vesicle trafficking.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CHS1/LYST/Beige is clearly involved in maintaining
lysosome-related organelle morphology. A recent study
used a proteomic approach to examine the components of
lysosomes from wild type and beigej liver based upon the
hypothesis that there may be informative differences in
the components of the lysosomes [87
]. The investigators
reported increased amounts of endoplasmic reticulum
proteins and reduced levels of late endosome/lysosome
protein Lamp2 in beigej lysosomes compared with wild
type lysosomes. The authors suggest that these data
reflect inappropriate incorporation of these proteins into
lysosomal membranes or ineffective removal or recycling
of these proteins during ‘normal’ membrane trafficking in
the absence of CHS1/LYST/Beige.
The cloning of the CHS1/LYST/Beige gene has allowed
for further analysis of the function of this protein. Beige
overexpression suggests that this protein is involved in
regulating vesicle size and trafficking, as overexpression
results in smaller than normal lysosomes localized to the
periphery of cells [88]. A yeast two-hybrid screen, using
parts of the CHS1/LYST/Beige gene as bait, identified
several interacting proteins involved in vesicle trafficking
[89]. These proteins included hepatocyte growth factor-
regulated tyrosine kinase substrate (HRS), 14-3-3, casein
kinase II and LIP5. HRS has been shown to be involved
in the sorting of ubiqutinated membrane proteins mark-
ing them for trafficking through the multivesicular body
to the lysosome [90]. 14-3-3 binds to signaling proteins,
including phosphatases, kinases and membrane recep-
tors, and affects their trafficking [91]. Casein kinase II is
known as an important signaling molecule and has been
implicated in a wide range of intracellular processes [92].
LIP5 is a protein required at the terminal stages of
multivesicular body formation [93–97]. The two-hybrid
screen along with a dominant negative Beige truncation
analysis [98] has suggested that the CHS1/LYST/Beige
protein interacts with several different proteins and that
those interactions require the full-length protein for
function.
Conclusion
CHS is a lethal human disorder that affects lysosome-
related organelle morphology and function. Although
the mutant gene responsible for CHS was identified
over 10 years ago, the role of CHS1/LYST/Beige is
still unknown. The identification of the BEACH
family of proteins and the studies performed in model
organisms have advanced our knowledge of different
biochemical pathways in which BEACH proteins are
involved. All of the biochemical defects associated with
mutant or deleted BEACH proteins can be ascribed to
vesicular trafficking defects, defining the BEACH
family of proteins as vesicle trafficking regulatory
proteins.

Acknowledgements
This work is supported by NIH grant HL26922 to J.K.
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