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Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 979-983
IMMUNOBIOLOGY
Protein truncation test of LYST reveals heterogenous mutations
in patients with Chediak-Higashi syndrome
Stéphanie Certain,
Franck Barrat,
Elodie Pastural,
Françoise Le Deist,
Jose Goyo-Rivas,
Nada Jabado,
Malika Benkerrou,
Reinhard Seger,
Etienne Vilmer,
Gilles Beullier,
Klaus Schwarz,
Alain Fischer, and
Geneviève de Saint Basile
From the Unité de Recherche sur le développement normal
et pathologique du système immunitaire INSERM U429 et Unité
d'immuno-hématologie pédiatrique, Hôpital
Necker-Enfants Malades, Paris, France; Departamento de Puericultura y
Pediatria, Universidad de los Andes, Merida, Venezuela; Unité
d'Hématologie-Immunologie, Hôpital Robert Debré,
Paris, France; Abt. Immunologie/Hämatologie/Infektiologie,
Zürich, Switzerland; Service de pédiatrie, Hôpital
Gabriel Martin, Saint-Paul, France; and Transfusion Medicine,
University of Ulm, Germany.
 |
Abstract |
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive
disorder in which an immune deficiency occurs in association with
pigmentation abnormalities. Most patients who do not undergo bone
marrow transplantation die of a lymphoproliferative syndrome, though
some patients with CHS have a relatively milder clinical course of the
disease. The large size of the LYST gene, defective in CHS, has made it
difficult to screen for mutations in a large number of patients. Only 8 mutations have been identified so far, and all lead to a truncated LYST
protein. We conducted protein truncation tests on this gene in 8 patients with CHS. Different LYST mutations were identified in all
subjects through this approach, strengthening the observation of a high
frequency of truncated LYST proteins as the genetic cause of CHS.
(Blood. 2000;95:979-983)
© 2000 by The American Society of Hematology.
| |
Introduction |
Chediak-Higashi syndrome (CHS; MIM, 214 500) is an
autosomal recessive disease characterized by partial oculocutaneous
albinism, mild predisposition to pyogenic infections, and abnormally
large granules in many different cell types.1-3 A
patient's susceptibility to infection may be explained by defects
observed in T-cell cytotoxicity4 and natural killer cell
activity5,6 as well as in chemotaxis7 and
bactericidal capacity8,9 of granulocytes and monocytes. Unless they undergo allogenic bone marrow transplantation
(BMT),10 many patients with CHS die young because of the
so-called accelerated phase, which is characterized by the infiltration
of most organs with activated T lymphocytes and macrophages and by
pancytopenia and coagulation disorder.11 In some patients,
however, the disease takes a relatively milder clinical course and the
patients survive to adulthood with few or even no severe infections.
At the cellular level, enlarged vesicles or granules are easily
detected in the cytoplasm of most cell types. These structures are
preferentially perinuclear and are associated with impaired compartmentalization or sorting of many different lysosomal protein components, suggesting that CHS may involve defective trafficking of
specific proteins to organelles.4,12
A similar disorder is reported in other species,13
including mice (beige mouse), minks (Aleutian), rats, cats,
cows, and whales. Mutants in all species examined have similar
morphologic features, such as altered size and altered distribution of
lysosomes.13 Manifestations of the accelerated phase,
however, have never been reported in animal models of
CHS.13 Homology between that disease in beige mice and CHS
was recently supported by the mapping of the CHS locus to chromosome
1q42-q43 in a segment corresponding to the beige locus region on mouse
chromosome 13.14,15 It was confirmed by the sequence
homology shared between the CHS and the beige coding sequence gene
(LYST).16-18 The full-length human LYST gene coding segment
encompasses 13.5 kb and encodes a predicted 3801 amino acid
polypeptide. Pathologic mutations in this gene have been reported in 9 patients.17,19,20 Interestingly, only nonsense mutations
and frameshifts of the LYST gene have been identified so far.
Considering the length of the LYST coding sequence and the unknown
genomic structure of this gene, the detection of mutations is a
technical challenge. We therefore established a protein truncation test
21-23 to look for mutations in LYST mRNA from 8 patients
with CHS. All the patients had premature termination codon mutations on
both alleles.
| |
Patients, materials, and methods |
Patients
All patients analyzed in this study fulfilled the criteria for the
Chediak-Higashi syndrome24: partial albinism with typical pigment clumping in the hair shaft, giant granulations easily detected
in polymorphonuclear cells, and defective cytotoxic activity of natural
killer cells. In 7 patients, the disease entered the accelerated phase
(Table 1). Informed consent was obtained
from patients or families for this study.
RNA extraction and reverse transcription/nested polymerase chain
reaction
Using standard techniques, total RNA was extracted as described
elsewhere19 from fibroblast cell lines or from Epstein-Barr virus-transformed lymphoblastoid cell lines established from patients with CHS. The entire coding region (13.5 kb) of the LYST gene was
reverse-transcribed in 9 overlapping nested reactions (mean size, 1.4 kb), and 1 µg RNA was used as a template for the first-strand cDNA
synthesis. Reverse transcription (RT) was performed according to the
manufacturer's (Roche Diagnostics, Neylan, France)
instruction from a specific reverse primer LYSTXR (X = 1-9) (Table
2) in a total volume of 20 µL. A 30-µL
polymerase chain reaction (PCR) mix containing primers LYSTXF (forward)
and LYSTXR (reverse) was then added to the RT reaction, and the first
round of amplification was performed, consisting of 40 cycles of
94°C for 1 minute, specific annealing temperature for each pair of
primers (see Table 2) for 1 minute, and 72°C for 5 minutes. A
2-µL aliquot of the RT-PCR was used in a subsequent round of nested
PCR (nested RT-PCR) using inner primers (T7-LYSTX'F and LYSTX'R)
(Table 2) in a final volume of 50 µL (30 cycles were performed as
above). The inner forward primers were designed to include a
translation initiation site and a T7 promoter sequence for the
initiation of transcription by T7 RNA polymerase. One
fifth of the nested RT-PCR reaction was analyzed on 1% agarose gel.
Protein truncation test.
Full-length RT-PCR products were subjected to the protein truncation
test (PTT) to search for truncated mutations. Peptides were produced in
the TNT-T7 Coupled Reticulocyte Lysate System (Promega, Lyon, France)
according to the manufacturer's instructions in the presence of
35S cysteine (Amersham, France) in a reaction volume of
12.5 µL. The derived protein products were separated on 12%
sodium dodecyl sulphate-polyacrylamide gels and detected by autoradiography.
Direct sequencing.
PCR products showing an abnormal pattern in the PTT analysis were
directly sequenced using dye terminator cycle sequencing kits on
an ABI 377 automatic sequencer (PE Applied Biosystems, Foster City,
CA). They were amplified using a forward primer identical to that used
in the PTT-PCR without the presence of the T7 polymerase binding site
and the start codon. Several mutations were sequenced in 2 different
cDNA preparations, and all the mutations were confirmed on the opposite
strand in at least 1 PCR. When blood samples from the patients'
parents were available, heterozygous mutations were determined by
direct sequencing of each specific LYST region that encompassed the
mutation(s) previously identified in the probands.
| |
Results |
Clinical phenotype
The 8 patients analyzed in this study belong to 7 different
families. Five patients are offspring of genetically related parents (Table 1). An accelerated phase occurred in 7 of these patients; in all
but 1, it occurred before they were 6 years of age (Table 1). The
accelerated phase was characterized in all by fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, and
fibrinopenia. In 5 of them (patients 1, 2, 3, 4, 5), it was
characterized by the presence of mononuclear cells in the cerebrospinal
fluid. In patient 2 the course of the accelerated phase was less
severe. Essentially it consisted of hepatosplenomegaly and mild
leucopenia that remained stable without treatment during the 6 months
preceding successful BMT. In 5 of these patients, occurrence of the
accelerated phase clearly correlated with Epstein-Barr virus (EBV)
infection. Either a high EBV-specific antibody response or the EBV
genome was detected at the time of onset; sometimes both were detected. In the 2 remaining patients, there was no assessment of EBV infection. Three patients died before (patient 5) or during (patients 1 and 8)
BMT, and 1 patient (patient 4) was successfully treated by BMT.
However, the total disappearance of donor cells was observed 11 years
later after transplantation, and the patient died of a new accelerated
phase before a second BMT could be performed. Three patients had milder
forms of the disease. Patients 7 and 3 had a single accelerated phase
at the age of 2 years and 14 years, respectively, that resolved rapidly
under specific treatment (corticoids in addition to etoposide or
cyclosporin A respectively) without further relapse to date (Table 1).
The accelerated phase never occurred in patient 6, who is now 10 years
old. This milder expression of CHS was not found in the other affected
siblings from the same families. Indeed, the brother of patient 6 (patient 5) died of a severe form of the disease before he was 2 years of age. Patient 7 had 1 younger sister and 1 cousin who died before they were 2 years of age and 3 other affected cousins aged 11, 16, and
40 years, who are still alive.
In 4 patients older than 10 years of age (patients 2, 3, 4, and 7) at
the time of investigation, mild to severe mental
retardation, including slow ideation in the first 3 patients, was
noted. School performance of these patients is poor (Table 1). In
addition to pronounced mental deficiency and poorly developed speech,
patient 3 has loss of muscle stretch reflexes, weakness, and distal atrophy.
Mutations
Full-length RT-PCR products for the 9 LYST overlapping fragments
were obtained from the cDNA of each CHS patient studied. The products
were then analyzed by PTT. All the patients exhibited an abnormal
electrophoresis pattern for 1 or 2 of the 9 RT-PCR fragments studied.
Truncated proteins were generated from cDNA fragment 3 from patients 1 and 2 (Figure
1), from cDNA
fragment 5 of patient 5 (for half the product), from cDNA fragment 6 of patient 4, from cDNA fragment 7 of patient 8, and from cDNA fragment 8 in the remaining patients (Table 3). No
peptide could be detected for patient 7 after in vitro transcription
and translation of fragment 8 (Figure 1). Slightly reduced band sizes
of fragment 8 were observed for the samples of patients 5 and 8 (Figure
1). For all patients except patient 5, the presence of a truncated protein was associated with the total disappearance of the
corresponding normal product. In each case, the size of the band made
it possible to localize the site of the mutation and to focus the
sequencing step. The absence of a peptide suggested a mutation located
at the 5' end of the RT-PCR fragment analyzed. Direct cDNA
sequencing using appropriate primers led, in each case, to the
identification of the disease-causing mutation. They consisted of a
nonsense mutation in patient 2, a 1-bp deletion in patients 1, 3, 5, and 8, or a deletion of several base pairs in most of the remaining patients, each of which led to a sequence frameshift (Table 3 and
Figure 2). On 1 allele, a 10-bp insertion was observed in patient 5. Both heterozygous mutations identified in patient 5 were also detected
in his sister (patient 6), whereas LYST cDNA of his father and mother
displayed the 5317 delA and the 10-bp insertion at nucleotide 9228, respectively. In the family of patient 1, further analysis enabled us
to demonstrate that the homozygous mutation identified in the proband
was the result of a LYST mutation inherited from his mother, associated
with a maternal, uniparental isodisomy of chromosome 1.25
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| Fig 1.
Mutation screening by protein truncation test.
PTT analysis shows abnormal fragment 3 pattern in patient 2 and
abnormal fragment 8 pattern in patients 5, 7, and 8 in comparison with
the control (Co). (dashes) Wild-type, full-length products. (arrows)
Abnormal bands. Nonspecific additional bands can be seen in some
samples. Marker and molecular weights of the marker proteins (in kd)
are shown on the right-hand side of the gels.
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|
View larger version (20K):
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| Fig 2.
Representation of the LYST gene mutations.
Schematic representation of the LYST protein with its known motifs
(HEAT and ARM repeats, BEACH domain, WD40 repeats), as previously
described.17 LYST gene mutations described herein
(underlined), as well as previously reported (italics), with their
respective references in parentheses, are listed.
|
|
In addition to the normal-sized product expected from the position of
the primers, shorter PCR products were also amplified in some patients
after the second PCR round, though at a less abundant level (data not
shown). After gel purification of the extra bands, direct cDNA
sequencing was performed. In each case, amplification started at the
5' or the 3' part of the expected product with unspecific
annealing of 1 primer. Sequence anomalies were still detectable when
corresponding shorter products were amplified. These additional PCR
bands probably accounted for the shorter PTT extra bands detected in
some of the samples. Thus any biologic relevance of these alternative
transcripts is unlikely.
| |
Discussion |
The lysosomal trafficking regulator (LYST) gene was recently
identified and was found to have mutated in patients with
Chediak-Higashi syndrome16,17 and in beige
mice.18 In each species, all the LYST gene alterations
published so far result in a truncated protein because of nonsense or
frameshift mutations.17,19,20 This observation in addition
to the large size of the LYST cDNA (13.5 kb), the complexity of the
gene, and the scattering of mutations across the coding sequence with
no apparent clustering detectedmakes PTT suitable for mutation
screening of the LYST gene.21-23,26 Furthermore, mutations
identified by PTT have immediate clinical relevance, whereas amino acid
substitutions might still turn out to be false positive as a result of
rare polymorphisms with no causal relationship to the disease
phenotype. We thus established the technical conditions necessary to
study LYST gene mutations by using this approach, and we analyzed 8 patients with CHS in 7 different families.
PTT analysis enabled us to identify mutations in all the patients
studied. Six mutations were homozygous at the protein and at the
nucleic acid sequence levels (Table 3). Four mutations occurred in
patients from consanguineous families. In the remaining patient, the
homozygous mutation was the result of a maternal chromosome 1 isodisomy
inherited from a heterozygous carrier mother.25 In sibling
patients 5 and 6, 2 heterozygous mutations inherited from each of their
unrelated parents led to a stop codon. Thus, in addition to the 9 patients with CHS previously reported in the
literature,16,17,19,20 the LYST gene mutations identified in the 7 families reported herein also exhibited truncations of the
LYST protein (Figure 2). These results justify the use of PTT for rapid
analysis of this huge gene. They also suggest that missense
substitutions in the LYST gene may result in a milder phenotype, a
different clinical phenotype, or the absence of any phenotype. These
should be determined by studying a larger series of patients.
Alternatively, these results may indicate that the presence of the
terminal part of the LYST protein, which contains the WD40 motifs
suspected to play a role in protein-protein interaction, may be a
determining factor in the function of the LYST protein. Analysis of
additional patients would help to answer these intriguing questions.
Although the immunologic defect in CHS implicates
defective chemotaxis of granulocytes, delayed intracellular
microorganism killing, and lack of natural killer cell cytotoxic
activity, some of these features are inconstantly observed in the
patients and are probably not directly responsible for the severity of
this disorder. The primary immunologic symptom that determines the prognosis of CHS is the accelerated phase. It has been reported that
the onset of the accelerated phase and the patient's age at onset are
key prognostic factors of CHS.2 Our results strengthen this
observation. Among the 6 patients in whom the accelerated phase
occurred before the age of 6, 5 died after the initial onset (4 patients) or a relapse (1 patient). Only 1 patient had early onset and
no relapse 9 years later. In contrast, each patient with no or late (14 years of age) development of the accelerated phase is still alive
without having undergone BMT.
A clear correlation between genotype and accelerated phase occurrence
was not observed among this limited number of patients. Indeed, within
a given family, variation in the severity of the phenotypic expression
of CHS can be observed. Patient 5 died at the age of 18 months during
the course of an accelerated phase, whereas his older sister is still
immunologically asymptomatic at 10 years of age. In her, the diagnosis
was made only because of the diagnosis of CHS in her younger brother. A
similar observation was made in the family of patient 7. Two affected
siblings died after onset of the accelerated phase before they were 2 years of age, whereas 3 other relatives who did not undergo BMT and have not had symptoms of the accelerated phase are still alive at 11, 16, and 40 years of age. In addition, variations in the phenotypic
expression of the disease can be observed among unrelated patients with
identical LYST mutations. Patient 2, in whom the accelerated phase
occurred at the age of 2 years, shares a mutation with a previously
reported patient who had late-onset CHS expression.17 Finally, it is striking to note that the phenotypic expression of this
disease does not seem to correlate with the length of the residual LYST
truncated protein. In both patients with terminal truncation of the
LYST protein, classical severe expression of the disease was observed,
whereas less severe forms were observed in patients with more proximal
truncations (patients 3 and 7). However, studying additional patients
and better determining the functional domains of the LYST protein are
necessary to draw definitive conclusions about the phenotypic
consequences of these mutations.
These data indicate that neither the clinical expression in another
family nor the determination of that family's mutation can easily help
in therapeutic decisions; the overall outcome of CHS is generally poor.
These data also indicate that other factors of genetic or environmental
origin could modify the clinical expression of CHS. In this respect, it
is worth noting the role of EBV infection as a trigger of the
accelerated phase. To some extent, variability in the accelerated phase
is reminiscent of the most variable outcome of X-linked
lymphoproliferation, a genetic condition in which the
SAP/SH2D1A/DHSP27-29 gene defect often leads to a condition
phenotypically close to the accelerated phase of CHS once patients have
been infected by EBV. Additional studies of patients with CHS are
required to assess better the roles of LYST mutations on the function
of this protein and of other intervening factors in the outcome of the disease.
| |
Acknowledgments |
We thank the families involved in the study for their cooperation. We
also thank Drs M. Duval, F. Bertey, W. Friedrich, and the physicians of
the Department of Pediatric Immunology and Hematology, Hôpital
Necker-Enfants Malades, for their part in the recruitment and follow-up
of patients. We thank S. Tuffery for helpful technical discussions
regarding PTT.
| |
Footnotes |
Submitted April 28, 1999; accepted September 30, 1999.
Supported in part by grants from l'Institut National de la Santé
et de la Recherche Médicale (INSERM), l'Association Vaincre les
Maladies Lysosomiales, l'Association Française contre les Myopathies, l'Assistance Publique Hôpitaux de Paris, and the CDCHT-ULAM-383-91 (Merida-Venezuela).
Reprints: Geneviève de Saint Basile, INSERM U429,
Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris, Cedex 15, France; e-mail: sbasile{at}necker.fr.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction