Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1493-1498
RED CELLS
The IVS4 + 4 A to T mutation of the Fanconi anemia gene
FANCC is not associated with a severe phenotype in Japanese
patients
Makoto Futaki,
Takayuki Yamashita,
Hiroshi Yagasaki,
Tatsushi Toda,
Miharu Yabe,
Shunichi Kato,
Shigetaka Asano, and
Tatsutoshi Nakahata
From the Departments of Pediatrics and Hematology/Oncology,
Institute of Medical Science, University of Tokyo, Tokyo,
Japan; Laboratory of Genome Medicine, Human Genome Center,
Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
the Department of Pediatrics, Tokai University School of Medicine,
Isehara, Japan.
 |
Abstract |
Fanconi anemia (FA) is an autosomal recessive disease characterized
by congenital anomalies, aplastic anemia, and a susceptibility to
leukemia. There are at least 8 complementation groups (A through H).
Extensive analyses of the FA group C gene FANCC in Western countries revealed that 10% to 15% of FA patients have mutations of
this gene. The most common mutation is IVS4 + 4 A to T (IVS4), a
splice mutation in intron 4, which has been found only in patients of
Ashkenazi Jewish ancestry. When we screened 29 Japanese patients (20 unrelated patients and 4 families) using polymerase chain reaction-single strand conformation polymorphism, we found 8 unrelated patients homozygous for IVS4. This is apparently the first
non-Ashkenazi-Jewish population for whom this mutation has been
detected. The Ashkenazi Jewish patients homozygous for IVS4 have a
severe phenotype, in comparison with other FA patients. Our analyses of
Japanese patients indicate no significant difference between IVS4
homozygotes and other patients with regard to severity of a clinical
phenotype. Thus, ethnic background may have a significant effect on a
clinical phenotype in FA patients carrying the same mutation.
(Blood. 2000;95:1493-1498)
© 2000 by The American Society of Hematology.
| |
Introduction |
Fanconi anemia (FA) is an autosomal recessive genomic
instability syndrome characterized by progressive bone marrow failure, congenital anomalies, and cancer susceptibility.1,2 Cells derived from FA patients show hypersensitivity to DNA cross-linking agents, abnormal cell cycle progression, and reduced cell
survival.3-5 FA patients constitute at least 8 different
complementation groups (FA-A to FA-H), as defined by cell fusion
analysis.5-8 The genes for group C (FANCC), group A
(FANCA), and group G (FANCG) have been cloned by other
investigators.9-12 While the cellular functions of proteins
encoded by these genes are unknown, the proteins bind in a nuclear
complex, suggesting that they cooperate in a nuclear function, such as
DNA repair.13-15
The coding sequence of the FANCC gene is composed of 14 exons
and encodes a protein of 558 amino acid residues with a molecular mass
of 63 kd. Extensive analyses of the gene in Western
countries revealed at least 9 mutations in this gene.16-19
Mutations in most patients cluster in 3 regions of the gene: exon 1, intron 4, and exon 14. The most common mutation is IVS4 + 4 A to T
(IVS4), a splice mutation in intron 4 resulting in deletion of exon
4.17,18 Less common mutations include 322delG, a frameshift
generating a premature stop codon, and Q13X in exon 1, and R548X and
L554P in exon 14.16,18,19
The percentages of group A and group C patients in Western countries
are estimated to be 60% to 65% and 10% to 15%,
respectively.20 However, it was reported that genetic
abnormalities for FA vary among different ethnic groups. About 80% of
Ashkenazi Jewish patients are assigned to group C.17
On the other hand, the proportion of group C patients in non-Jewish
populations is reported to be about 8%.16 Group A patients
are more prevalent in Germany and Italy,21,22 whereas the
majority of patients in the Netherlands belong to group
C.21 FANCC mutation types differ among distinct ethnic groups. The IVS4 mutation is unique to Jewish patients, whereas
322delG is often present in patients of Northern European ancestry.16,17 Genotype-phenotype analyses in FA patients
revealed that Ashkenazi Jewish patients with the IVS4 mutation have the severe clinical phenotype, such as early onset of
hematological diseases, multiple major malformations, and poor
survival, in comparison with other group C patients with exon 1 mutations or non-C patients.18,23,24
Little is known of the genetic basis of FA patients in Asian
countries. In the present work, we screened FANCC mutations in 29 Japanese patients and identified 8 patients homozygous for the IVS4
mutation. Our analyses show that these patients have a clinical
phenotype similar to that in other patients, unlike Ashkenazi Jewish
patients with the same mutation.23 The present findings
provide important information for population-based screening for
FANCC carriers in Japan and genotype-phenotype relationship in
group-C FA patients.
| |
Materials and methods |
We diagnosed 29 Japanese patients with 25 probands on
the basis of the presence of clinical manifestations of FA
(hematological abnormalities and/or congenital anomalies typical of FA,
as defined by Auerbach et al3) and on the basis of studies
on the chromosomal breakage induced by diepoxybutane or mitomycin C in
peripheral blood lymphocytes.
Onset of hematological abnormalities is defined as the time at which
one of the following laboratory parameters was observed: platelet count
below 100 × 109/L, hemoglobin (Hb)
below 10 g/dL, or absolute neutrophil count below
1 × 109/L.
Patients were scored for the presence of major congenital
abnormalities, defined as structural alterations that occur during embryogenesis, with medical and social consequences. The spectrum of
major congenital malformations in FA patients included abnormalities of
the kidney and urinary tract, genitalia, heart, gastrointestinal system, and central nervous system and skeletal abnormalities, including defects of the radius and thumb.
To screen for the FANCC gene, we used polymerase chain reaction
(PCR)-single strand conformation polymorphism (SSCP). We obtained genomic DNA samples from the peripheral blood of our patients and from
normal healthy volunteers. All of the subjects gave informed consent.
Each coding exon of the FANCC gene was amplified by the PCR
with the use of genomic DNA and primers flanking the individual exons
and overlapping the intron-exon boundaries, as described by Gibson et
al.25 PCR-SSCP analysis was performed according to the
methods described by Orita et al.26 Briefly, a total of 10 µL of reaction mixture, containing 200 ng of genomic
DNA, 0.4 pmol of each primer end-labeled with [
-32P]
ATP (Amersham), 100 µmol/L
dNTPs, 10 mmol/L Tris-HCl(pH 8.3), 50 mmol/L KCl, 1.5 mmol/L MgCl2,
0.001% gelatin, and 0.2 U of Taq polymerase
(Perkin-Elmer) was used for PCR amplification. PCR
reactions were performed for 1 step of denaturation (5 minutes at
94°C), followed by 35 cycles of denaturation (30 seconds at 94°C), annealing (30 seconds at 60°C), extension (40 seconds at 72°C), and a final step of extension (7 minutes at 72°C). Then, 5 µL of the PCR products was diluted in 45 µL of formamide loading buffer (90% formamide, 10 mmol/L ethylenediaminetetraacetic acid, 0.25% bromphenol blue, 0.25%
xylene cyanol). The mixture was heated to 80°C for 5 minutes to
denature the DNA, then rapidly chilled on ice. An aliquot of the sample
(2 µL) was analyzed on a 6% nondenaturing polyacrylamide gel (49:1 acrylamide : bisacrylamide),
with or without 10% glycerol in 0.5 × TBE buffer. Gels
containing 10% glycerol were run at room temperature at 10 W for 14 hours and gels without glycerol were run for 4 hours at 4°C at
40 W. The gels were then dried and autoradiographed.
Mutations were characterized by direct sequencing of PCR products. When
shifted bands were obvious on the SSCP gel, these bands were excised
and eluted from the gel and then used as a template for PCR. Cycle
sequencing reactions were performed with the use of Taq Dye Terminator
Cycle Sequencing Kits (Perkin-Elmer). Sequencing was done with an
automated sequencer (ABI model 310; Perkin-Elmer).
Allele-specific oligonucleotide (ASO) hybridization was performed as
follows: Genomic DNA was used as template for PCR, with the following
primers flanking exon 4:5'-GTAGGCATTGTACATAAAAG-3' (forward
reaction) and 5'-TGGCACATTCAGCATTAAAC-3'
(reverse reaction). The PCR product was dot-blotted onto
nylon filters (Hybond N, Amersham) and hybridized with end-labeled
oligonucleotides with [-32P] ATP
corresponding to the wild-type or mutant sequence at intron 4, 5'-AAAATGTGAGTATTT-3' or
5'-AAAATGTGTGTATTT-3', respectively. Hybridizations were
performed at 30°C for 3 hours, followed by washing for 10 minutes
in 2 × SSPE, 0.1% sodium dodecyl sulfate (SDS) at room
temperature, then by a 10-minute wash at 32°C in 0.2 × SSPE, 0.1% SDS.
For the statistical analysis, we used StatView 4.5 software. Unpaired
Student t test was used to compare the age at onset of
hematological abnormalities and the anomaly number between patients
with IVS4 mutation and other patients.
| |
Results |
First, we amplified 14 segments covering each exon of FANCC
from genomic DNA isolated from 29 FA patients and analyzed by SSCP. In
samples from 8 patients (P1 through P8), PCR products corresponding to
exon 4 and flanking intronic regions showed aberrant bands.
Representative data of 6 patients (P1 through P6) are shown in Figure
1A. Similar aberrant bands were seen in
4510 cells known to be homozygous for the IVS4 + 4A to T
mutation, suggesting that 8 of the 29 patients carry this
mutation. A sample from one patient, P21, showed both normal and
aberrant bands, like a sample from FA239 cells known to
be heterozygous for the IVS4 mutation. In none of the 29 samples did we
detect mobility shifts of other segments (data not
shown), while we did detect mobility shifts in control
samples known to have 322delG and L554P mutations (data not shown).
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| Fig 1.
Detection of IVS4 mutation by PCR-SSCP and subsequent
direct sequencing.
(A) Representative PCR-SSCP analyses using the primer set for exon 4 boundaries. 4510C cells are homozygous for the IVS4 mutation; FA239
cells are heterozygous (IVS4/wt) for this segment; and N indicates
normal control. The patient numbers correspond to those in Table 1.
Arrowheads indicate mobility shifts of the PCR products from the
genomic DNA from the patients, P1, P2, P3, P4, P5, and P6. (B)
Representative sequencing results. Direct sequencing of aberrant bands
from P1 identified an A to T transition of the fourth base in intron 4 (indicated by arrows).
|
|
Direct sequencing of PCR products showing the mobility shift identified
the IVS4 mutation in all of the samples from patients 1 through 8. Figure 1B shows representative data from a normal control and P1. A
sample of P21 showed a normal sequence as well as the mutation (not
shown), suggesting that this patient may be a compound heterozygote,
although the other FANCC mutation was not detected.
To confirm that the 8 patients (P1 through P8) are homozygous for the
IVS4 mutation, we next carried out ASO hybridization (Figure
2), as described.17 DNA samples
from normal cells hybridized to the wild-type ASO but not to the mutant
ASO, whereas a sample from 4510 cells homozygous for the IVS4 mutation
only hybridized to the mutant ASO. A sample from FA239 heterozygous
cells hybridized to both probes. DNA samples from P1, P3, P4, P5, P6,
and P7 hybridized with the mutant oligonucleotide but not with the
normal oligonucleotide (Figure 2). DNA samples from P2 and P8 gave
similar results (data not shown). These results indicate that both
alleles of the 8 patients have IVS4 mutation.
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| Fig 2.
Allele-specific oligonucleotide hybridization for IVS4.
Hybridization of the wild-type or mutant oligonucleotide to DNAs from
the FA patients with the IVS4 mutation (P1, P3, P4, P5, P6, and P7) and
control cells. 4510C cells are homozygous for the IVS4 mutation; FA239
cells are heterozygous (IVS4/wt) for this segment; and N indicates
normal control.
|
|
The clinical characteristics of the 29 patients, 8 patients homozygous
for the IVS4 mutation (group I) and the other 21 patients (group II),
are summarized in Table 1. There is no
consanguinity or geographical isolation of the patients with IVS4.
Previous studies showed that patients homozygous for IVS4 have a severe phenotype, as manifested by early onset of hematological disease and
multiple major congenital anomalies.18,23,24 Therefore, we
compared the age at onset of the hematological disease and the number
of major congenital malformations between groups I and II. The median
age at onset of hematological disease was 6.21 years (95% confidence
interval [CI], 2.88 to 9.54 years) in group I and 5.79 years (95%
CI, 4.14 to 6.44 years) in group II (Table 2), suggesting no significant difference
between the 2 groups. There was also no significant difference between
the 2 groups in the mean number of major congenital anomalies (1.3 in
group I versus 1.1 in group II) (Table 2) or the distribution of
patients with each number of major anomalies (Figure
3). Taken together, these results suggest
that the severity of a clinical phenotype is similar between IVS4
homozygotes and other FA patients. Table 2 also shows the results of a
previous study23 indicating that Ashkenazi Jewish IVS4
patients have an earlier onset of hematological abnormalities and a
greater number of major congenital anomalies in comparison with other
patients.
Gillio et al also found that survival time of Ashkenazi Jewish
patients with IVS4 is short in comparison with patients with the
322delG mutation of FANCC and non-C patients, partly because of
the early development of leukemia.23 In the present study, 2 of the 8 patients (25%) in group I developed myelodysplastic syndrome, and 6 of 21 patients (28%) in group II had myelodysplastic syndrome or acute myeloid leukemia (Table 1). Thus, there is no
significant difference with regard to disease progression. We cannot
compare survival time of the 2 groups, partly because follow-up time
was short. Another reason is the difference of treatment for the 2 groups; all the patients with IVS4 were treated with allogeneic bone
marrow transplantation, whereas only 5 of the other patients underwent
this treatment.
| |
Discussion |
In the first report describing IVS4 + 4A to T, the mutation was
found in 5 Ashkenazi Jewish families and not found in any non-Jewish
families.17 Analysis of patients in the International Fanconi Anemia Registry confirmed that this mutation is responsible for
most cases of FA in Jewish patients; all of the families with this
mutation have a Jewish heritage, and 16 of 20 Jewish FA families tested
have this mutation.18 On the other hand, FA patients of
non-Jewish ancestry did not have this mutation. Thus, the IVS4 mutation
is referred to as the Ashkenazi Jewish mutation.27 In the
current study, we found 8 homozygotes and 1 heterozygote with the IVS4
mutation among 29 Japanese patients. This is apparently the first
report that the IVS4 mutation was identified in a population of
non-Ashkenazi-Jewish origin.
In the current study, the IVS4 mutation was the only mutation found in
our Japanese FA patients, although our screening method PCR-SSCP
detects 70% to 80% of mutations26 and may have missed less common FANCC mutations. Two groups recently reported that most of Japanese FA patients have various types of FANCA
mutations,28,29 suggesting that many of our non-C patients
belong to group A. Possibly, the group A and group C patients in Japan
have different ethnic backgrounds. However, it is difficult to address
this question, because there is no obvious marker to identify ancestry
in most of the Japanese. Modern Japanese populations have resulted from an intermingling of aboriginal people and immigrants from Korea or
mainland China that started more than 2000 years ago.30
Extensive screening in Asian countries using a rapid and readily
facilitated assay to detect the specific mutation, such as the
amplification refractory mutation system,27 may aid in
identifying the origin of the mutation in Mongoloids.
It is likely that the IVS4 mutation derived from a
founder and has expanded by a genetic drift in a small isolated
population. However, there is no definite evidence for a founder effect
in the Ashkenazi Jewish patients. In an attempt to search for a founder haplotype, we analyzed 4 microsatellite markers (D9S280, D9S1816, D9S1851, and D9S287) that are mapped within 1.8 cM around the FANCC
gene31,32 but found no founder haplotype (data not
shown). The Japanese IVS4 mutation is likely to have arisen
independently of the Ashkenazi Jewish mutation. IVS4 carriers are
detected in the Ashkenazi Jewish population but not in the Iraqi Jewish
population, suggesting that the mutation in the Ashkenazi population
arose after it separated from other Jewish populations as recently as 500 years ago.27 Thus, this mutation site appears to be a
relative hot spot.
FA is characterized by a wide variety of clinical
phenotypes.33 A clinical phenotype is associated, at least
in part, with specific FANCC mutations within group-C FA
patients.18,23 Patients with the IVS4
mutation or mutations in exon 14 (R548X or L554P) have a severe
clinical phenotype, early onset of hematological abnormalities,
multiple congenital anomalies, and short survival time, in comparison
with patients with 322delG or non-C FA patients.18,23 On
the other hand, our findings in the Japanese patients strongly suggest
that the IVS4 mutation is not associated with a severe phenotype. The
frequencies of congenital anomalies we noted were compared with
results described by Verlander et al18 (Figure 4). This figure clearly shows that
frequencies of most major anomalies are much higher in Ashkenazi Jewish
patients than in Japanese patients, whereas frequencies of skin
pigmentation and thumb/radius anomalies are similar in the 2 ethnic
groups. On the other hand, the frequencies of major anomalies, except
for thumb/radius defects, are comparable between other FA patients
(mostly non-C) in our study and patients with other FANCC
mutations (mostly 322delG) in the study by Verlander et
al.18 Therefore, the clinical phenotype of FA is affected
by ethnic background even among patients with the same IVS4 mutation.
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| Fig 4.
Frequencies of major anomalies in IVS4 homozygotes and
other patients.
This compares (A) the present study and (B) a previous
study.18 Part B was based on data shown in Table 3 in
Verlander et al.18 However, patients with D195V and L554P
were excluded because the pathogenic significance of D195V remains to
be established16 and L554P was later shown to be associated
with the severe clinical phenotype.23
|
|
A possible interpretation of these results is that genetic or
environmental factors protect against a severe phenotype in Japanese
patients with IVS4. Conversely, a severe phenotype of Ashkenazi Jewish
patients with IVS4 could be, at least in part, attributed to the ethnic
background. Since patients with this mutation were confined to
Ashkenazi Jews and the other patients in the previous studies were
non-Ashkenazi Jews,17,18,23 it is difficult
to determine whether a severe phenotype is due to the mutation, the
ethnic background, or both.
There are many instances of identical mutations associated with
phenotypic variation.34 This phenomenon was observed among unrelated individuals, within a family, and even in monozygotic twins.
However, little has been documented regarding the phenotypic variation
of genetic diseases among different ethnic groups. A similar event can
be seen in case of Gaucher disease. Earlier reports demonstrated that a
homozygous mutation resulting in an L444P transition in the
glucocerebrosidase gene is closely associated with a neuronopathic form
of Gaucher disease in the United States and a small population in
Sweden.35,36 By contrast, homozygotes for this mutation are
frequent in the nonneuronopathic form of patients in
Japan.37 This discrepancy may be attributed to differences in ethnic backgrounds of the patients.
Several mechanisms may be involved in phenotypic variation among
patients with an identical genotype: additional intragenic sequence
alteration; modifier genes at other loci; genetic background in
general, epigenetic mechanisms such as methylation and genomic imprinting; stochastic effects; influences of environment; and so
forth.34 However, no specific molecular basis has been
identified. To study cellular or molecular mechanisms for phenotypic
variation of FA between the Ashkenazi Jewish population and the
Japanese may elucidate the pathophysiologic basis of the clinical
phenotype of FA.
| |
Acknowledgments |
The following institutions and investigators participated in this
study: Ibaraki Children's Hospital (M. Tsuchida); Saitama Children's Hospital (R. Hanada); Chiba
Children Hospital (Y. Okimoto, N. Kinugawa);
Osaka University (J. Hara, Y. Nakanishi); Japan Red Cross Hiroshima
Hospital and Atomic Bomb Survivors Hospital (K. Hamamoto); Hiroshima University (K. Ueda); Kyushu Cancer Center (S. Okamura); Kagoshima City Hospital (K. Muraoka). We are
grateful to H. Joenje for providing the FA239 cell line, A. D. D'Andrea and J. Liu for helpful comments on the manuscript, and M. Ohara for language assistance.
| |
Footnotes |
Supported by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports and Culture of Japan and by grants from
the Ministry of Health and Welfare of Japan.
Submitted May 25, 1999; accepted October 19, 1999.
Reprints: Takayuki Yamashita, Department of
Hematology/Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639; Japan; e-mail: y-taka{at}ims.u-tokyo.ac.jp.
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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Gaucher disease type III (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene.
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Masuno M, Tomatsu S, Sukegawa K, Orii T.
Non-existence of a tight association between a 444 leucine to proline mutation and phenotypes of Gaucher disease: high frequency of a Nci I polymorphism in the non-neuronopathic form.
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[Order article via Infotrieve].
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Abstract
Introduction
