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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2261-2266
ERGIC-53 Gene Structure and Mutation Analysis in 19 Combined Factors V and VIII Deficiency Families
By
William C. Nichols,
Valeri H. Terry,
Matthew A. Wheatley,
Angela Yang,
Ariella Zivelin,
Nicola Ciavarella,
Caterina Stefanile,
Tadashi Matsushita,
Hidehiko Saito,
Norma B. de Bosch,
Arlette Ruiz-Saez,
Argimiro Torres,
Arthur R. Thompson,
Donald I. Feinstein,
Gilbert C. White,
Claude Negrier,
Christine Vinciguerra,
Melih Aktan,
Randal
J. Kaufman,
David Ginsburg, and
Uri Seligsohn
From the Division of Human Genetics, Children's Hospital Medical
Center, Cincinnati, OH; Howard Hughes Medical Institute and Departments
of Medicine, Human Genetics, and Biological Chemistry, University of
Michigan, Ann Arbor, MI; Institute of Thrombosis and Haemostasis, The
Chaim Sheba Medical Center, Tel-Hashomer and Sackler Faculty of
Medicine, Tel Aviv, Israel; the Department of Blood Coagulation and
Hemophilia Centre, University Hospital, Policlinico, Bari, Italy; Aichi
Blood Disease Research Foundation and The First Department of Internal
Medicine, Nagoya University School of Medicine, Nagoya, Japan; Centro
Nacional de Hemofilia, Banco Municipal de Sangre, Caracas, Venezuela;
the Puget Sound Blood Center and Department of Medicine, University of
Washington, Seattle, WA; the Department of Medicine, University of
Southern California School of Medicine, Los Angeles, CA; the Department
of Medicine, University of North Carolina, Chapel Hill, NC; Edouard
Herriot University Hospital, Department of Hematology, Lyon, France;
and the Department of Internal Medicine, Istanbul School of Medicine,
Istanbul, Turkey.
 |
ABSTRACT |
Combined factors V and VIII deficiency is an autosomal recessive
bleeding disorder associated with plasma levels of coagulation factors
V and VIII approximately 5% to 30% of normal. The disease gene was
recently identified as the endoplasmic reticulum-Golgi intermediate
compartment protein ERGIC-53 by positional cloning, with the detection
of two founder mutations in 10 Jewish families. To identify mutations
in additional families, the structure of the ERGIC-53 gene was
determined by genomic polymerase chain reaction (PCR) and sequence
analysis of bacterial artificial chromosome clones containing the
ERGIC-53 gene. Nineteen additional families were analyzed by direct
sequence analysis of the entire coding region and the intron/exon
junctions. Seven novel mutations were identified in 10 families, with
one additional family found to harbor one of the two previously
described mutations. All of the identified mutations would be predicted
to result in complete absence of functional ERGIC-53 protein. In 8 of
19 families, no mutation was identified. Genotyping data indicate that
at least two of these families are not linked to the ERGIC-53 locus.
Taken together, these results suggest that a significant subset of
combined factors V and VIII deficiency is due to mutation in one or
more additional genes.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
COMBINED DEFICIENCY of coagulation
factors V and VIII is an autosomal recessive bleeding disorder with
greater than 89 cases reported since the original description by Oeri
et al in 1954.1-5 Affected individuals present with a
moderate bleeding tendency and plasma levels of factors V and VIII
(both antigen and activity) in the range of 5% to 30% of normal.
Combined factors V and VIII deficiency was initially mapped to the long
arm of chromosome 18.6-8 Recent positional cloning efforts
identified the disease gene as ERGIC-53, a component of the endoplasmic
reticulum (ER)-Golgi intermediate compartment (ERGIC) of previously
unknown function.9 This latter report identified two
different founder mutations: (1) a G insertion in codon 30 resulting in
a frameshift of the 510 amino acid protein product in all affected
individuals from five Middle Eastern Jewish families and (2) a splice
donor mutation in intron 9 in all affected individuals from five
Sephardic Jewish families. Immunofluorescence studies and Western
analysis using Epstein-Barr virus (EBV)-immortalized B lymphocytes from affected individuals confirmed the absence of detectable ERGIC-53 antigen.
Although the function of ERGIC-53 is unknown, it is a type 1 transmembrane protein with homology to leguminous lectins that exhibits
mannose-selective and calcium-dependent binding and has been
hypothesized to play a role in the transport of glycoproteins through
the secretory pathway.10-14 The demonstration that its deficiency results in decreased plasma levels of coagulation factors V
and VIII suggests an important role for ERGIC-53 in ER to Golgi transport and implies the existence of cargo-specific pathways within
the secretory system. Vollenweider et al15
have recently shown that mistargeting of ERGIC-53 to the ER
impairs the secretion of the lysosomal enzyme cathepsin C, although
transport of two other lysosomal enzymes and three post-Golgi membrane
glycoproteins was unaffected. These results suggested that the
recycling of ERGIC-53 between the ERGIC and ER is required
for the intracellular transport of only a small subset of
glycoproteins. The common features shared between coagulation factors V
and VIII and other potential ERGIC-53-dependent proteins remain to be determined.
We now report the gene structure for ERGIC-53, as well as mutation
analysis for an additional 19 combined factors V and VIII deficiency
families. Seven new mutations were identified in 10 of 19 families. In
all except one of these families, the affected individual(s) was
homozygous for the mutation. One affected individual from a
nonconsanguineous family is a compound heterozygote, although the
mutation has been identified on only one allele. All of the mutations
would predict complete deficiency of a normal ERGIC-53 product. In
addition, one of the families was shown to carry the Middle Eastern
Jewish founder mutation.9 Failure to identify a mutation in
eight families, taken together with clear evidence against linkage to
the ERGIC-53 locus in two of these families, suggests that a
significant subset of combined factors V and VIII deficiency is due to
mutations in one or more additional genes.
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MATERIALS AND METHODS |
ERGIC-53 Gene Structure
Polymerase chain reaction (PCR) and sequence analysis of bacterial
artificial chromosomes and total human genomic DNA.
Either 2 nanograms of bacterial artificial chromosome (BAC) clones
293H21 or 65B23 (Research Genetics, Huntsville, AL) purified as
previously described9 or 20 ng of total human genomic DNA was amplified in a 50-µL reaction containing 200 µmol/L each
dNTP, 50 to 100 ng each primer, 1X PCR buffer (50 mmol/L
KCl, 10 mmol/L Tris, pH 9.0, 1.5 mmol/L MgCl2, 0.01%
gelatin, 0.1% Triton X-100), and Taq DNA polymerase. PCR was performed
for 35 cycles using an MJ Research PTC-100 96V thermocycler (MJ
Research, Watertown, MA). Forward and reverse primers were synthesized
from the ERGIC-53 cDNA sequence (GenBank X71661) and used in various
combinations to determine the location of introns. PCR products were
separated by electrophoresis through agarose and visualized by ethidium bromide staining. Any PCR product whose length was longer than that
expected for the cDNA was assumed to contain an intron and was
subjected to DNA sequence analysis using the Thermo Sequenase radiolabelled terminator cycle sequencing kit (Amersham Life Science Products, Arlington Heights, IL).
Direct sequence analysis of BACs 293H21 and 65B23.
One microgram purified BAC DNA was directly sequenced using the Thermo
Sequenase radiolabeled kit as above (Amersham Life Science Products) in
a reaction containing the dITP nucleotide master mix and
20 ng of primer specific for the ERGIC-53 coding sequence. Numerous
reactions were performed, each with a different specific primer.
Cycling conditions were 35 cycles of denaturation at 94°C for 30 seconds, annealing at 50°C for 30 seconds, and extension at
60°C for 6 minutes. Sequencing products were electrophoresed through standard 8% sequencing gels at 100 W. After electrophoresis, the gels were fixed, dried, and exposed to Kodak Biomax
film (Eastman Kodak, Rochester, NY).
Mutation analysis in combined factors V and VIII deficiency
patients.
Twenty-forty nanograms of genomic DNA, prepared as previously
described,6 from individuals affected with combined factors V and VIII deficiency (factors V and VIII antigen and activity levels
<30% of normal) and their unaffected parents and siblings (when
available) from 19 unrelated families were amplified by PCR. The entire
coding region of ERGIC-53 was amplified in multiple PCR reactions using
25 ng (37.5 ng for exon 8) of the appropriate primers as listed in
Table 1. Exons 2 and 3 were amplified in a single PCR product as were
exons 9 and 10 using the forward primer for exon 2 or 9 and the reverse
primer for exon 3 or 10. Only a portion of exon 13 through the stop
codon was included in the amplification product. Cycling conditions
were 1 minute each of denaturation, annealing, and elongation for 35 cycles using an MJ Research PTC-100 96V thermocycler (MJ Research). PCR products were separated by electrophoresis through 4% agarose (3%
Nusieve; FMC Bioproducts, Rockland, ME, 1% BRL) to ensure presence of sufficient quantities for sequence analysis. PCR products were purified using the QIAquick PCR purification kit (QIAGEN, Santa
Clarita, CA) and eluted in 30 µL dH20. PCR products were sequenced on both strands, as described above, using the same primers
as for the PCR reactions.
Haplotype analysis.
Haplotype analysis for short tandem repeat markers flanking the
ERGIC-53 gene was performed as previously described.6
Haplotype analysis using ERGIC-53 intragenic polymorphisms was
performed by PCR and sequence analysis as described above.
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RESULTS |
ERGIC-53 Gene Structure
To determine the intron/exon boundaries of the ERGIC-53 gene, a
combination of human genomic and BAC DNA PCR and direct sequence analysis of BAC DNA was used. In previous studies to clone the combined
factors V and VIII deficiency gene, BAC clones 293H21 and 65B23,
obtained by screening a human genomic DNA BAC library (Research
Genetics), had been shown by Southern analysis to contain the largest
portions of the ERGIC-53 gene (data not shown) and were therefore used
in the PCR and direct sequencing studies.9 As seen in
Fig 1 and
Table 1, the ERGIC-53 gene contains 13 exons ranging in size from 59 bp (exon 7) to greater than 1,244 bp
(exon 13). Exon 13 encodes only amino acids 499-510 with the remaining greater than 1,200 bp corresponding to the 3' untranslated
sequence (UTR). The full size of the 3' UTR is unknown, as no
polyadenylation signal is present in the available cDNA
sequence.16 Exon 1 contains at least 21 bp of 5' UTR,
although the transcription start site has not been determined and the
existence of an additional upstream noncoding exon cannot be excluded.
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| Fig 1.
Structure of the ERGIC-53 gene and mutations identified
in combined factors V and VIII deficiency. Exons, indicated by
rectangles, are numbered from 1 to 13. The coding portion of the gene
is shaded, with the open portions of exons 1 and 13 representing the
5' UTR and 3' UTR, respectively. The exons, as well as
introns 2, 9, and 12, are shown to scale. The // in the remaining
introns indicates that the size was not determined. The locations of
the two founder mutations identified in 10 Jewish families9
are shown above (indicated by *), while the eight mutations detected by
sequence analysis in the 19 families of this study (see Table 2) are
shown below the gene.
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Table 1.
Location and Length of ERGIC-53 Exons and Sequences of
Primers Used to PCR Complete Coding Region of ERGIC-53 From Genomic
DNA
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Direct sequence analysis enabled the determination of the size and full
sequence for three introns. Introns 2, 9, and 12 were completely
sequenced (GenBank Accession numbers AF081867, AF081880, and AF081885)
and are 83, 132, 290 bp, respectively. PCR analysis indicates that
intron 1 is approximately 4 kb in length. The sizes of the remaining
introns were not determined. All sequence data obtained to date have
been deposited in GenBank under accession numbers AF081865, AF081866,
AF081867, AF081868, AF081869, AF081870, AF081871, AF081872, AF081873,
AF081874, AF081875, AF081876, AF081877, AF081878, AF081879, AF081880,
AF081881, AF081882, AF081883, AF081884, and AF081885.
Mutation Analysis in Combined Factors V and VIII Deficiency
Patients
We previously reported the identification of two founder mutations in
the ERGIC-53 gene in 10 Israeli families with combined factors V and
VIII deficiency.9 In the current study, we have analyzed
DNA samples from 19 additional unrelated families/individuals with the
disorder, including 7 families from Italy, 4 from Venezuela, 3 from
Japan,17 3 from the United States, and 1 each from France and Turkey. The entire coding region of the ERGIC-53 gene and all
intron/exon junctions were sequenced in all affected individuals, as
well as in selected obligate carrier parents and unaffected siblings of
the patients when available (a total of 39 individuals).
Results of the sequence analysis are summarized in
Table 2. A total of eight different
mutations were identified, accounting for 11 of 19 families. Seven of
the eight mutations are either nonsense or frameshift mutations
resulting in a truncated protein that would be predicted to lack normal
ERGIC-53 function. All but one of the affected individuals is
homozygous for their respective mutations, consistent with a high
frequency of consanguinity in these families. The affected individual
in family 2 is heterozygous for the exon 3 frameshift mutation with no
candidate mutation detected on the other allele, either in the ERGIC-53
coding region or the sequences flanking the intron/exon junctions. The
mutation detected in family 11, ins G85-89, is the same mutation
previously reported in five Middle Eastern Jewish
families.9 Haplotype analysis of DNA markers in this region
demonstrated that the mutation in the affected individual in this
family, also of Middle Eastern Jewish origin (Iranian-Jewish) is
carried on the same haplotype,6 consistent with a common
origin (data not shown).
A single, common mutation was identified in four of the seven Italian
families in our patient cohort (Table 2). The affected individuals in
these four families were homozygous for the only missense mutation
observed in our study. This results in the substitution of threonine
for the initiator methionine. The next methionine codon is not
encountered until exon 2 and is out of frame. This mutation should thus
result in the complete absence of ERGIC-53 expression in these
patients. In all four of the families, the mutation is carried on a
shared haplotype, again suggesting a founder effect.
A number of additional sequence differences also detected in the
ERGIC-53 gene were identified as likely polymorphisms or rare sequence
variants (Table 3). Most of these changes
were observed in numerous unrelated families and are likely to
represent common polymorphisms. The intron 6 polymorphism appears to be in complete linkage disequilibrium with the intron 7 polymorphism; that
is, the two polymorphisms are always inherited together with no
individual identified to carry only one.
Of note, all chromosomes sequenced to date contain a thymine at
nucleotide 457, not the adenine reported in the published cDNA16, resulting in a serine residue at position 153 in
place of the reported threonine. An independently reported sequence for
a mannose-specific lectin termed MR6012 is identical to ERGIC-53 except for the same serine for threonine substitution at
position 153. This suggests a sequencing or cloning artifact in the
original report, although a rare sequence variant in the source of the
cDNA library cannot be excluded.
Haplotype Analysis in ERGIC-53 Mutation-Negative Families
Shown in Fig 2 is haplotype analysis for
two of the eight families in our study for which no mutation was
detected in the entire ERGIC-53 coding sequence or intron sequences
flanking the intron/exon junctions. The affected siblings in family 16 inherited different ERGIC-53 alleles from their parents, indicating
lack of linkage to the ERGIC-53 gene. The parents of the affected
individual in family 13 are first cousins, making it likely that the
patient is homozygous for the same mutant allele inherited from the
carrier parents. However, the patient is heterozygous for four short
tandem repeat markers flanking the ERGIC-53 gene, as well as five of six intragenic polymorphisms. These results indicate that the mutations
responsible for combined factors V and VIII deficiency in these two
families are unlikely to lie within or near the ERGIC-53 gene.
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| Fig 2.
Haplotype analysis for two families in which no
ERGIC-53 mutation was detected. Affected individuals (shaded)
in family 16, shown at the left, were determined to differ at five
ERGIC-53 intragenic polymorphisms (Table 3). The + indicates the presence of the more common sequence, while the  indicates the presence of the polymorphism or rare sequence variant.
Individuals in family 13, shown at the right, were genotyped for four
short tandem repeat polymorphisms flanking the ERGIC-53
gene.6,9 Numbers represent basepair length of the PCR
products generated with primers flanking the repeat sequence. Both
parents and the affected individuals were also typed for six intragenic
polymorphisms (Table 3).
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DISCUSSION |
We report the identification of seven novel mutations in the ERGIC-53
gene in patients with combined factors V and VIII deficiency. Mutations
were identified in 11 of 19 families studied. One founder mutation, by
virtue of haplotype analysis, was identified in four of seven Italian
families. All patients, except one, are homozygous for the respective
mutation, consistent with the high frequency of consanguinity in these
families. The large number of families reported here and in the
accompanying report18 suggests that combined factors V and
VIII deficiency may be considerably more frequent than originally
suspected. However, consistent with previous reports,2-5
the majority of families in both studies are of Mediterranean/Middle Eastern origin. Taken together with the evidence for a founder effect
among Middle Eastern Jews9 (and this study), Sephardic Jews,9 Italians (this study), Iranians,18 and
Pakistanis,18 these data suggest the possibility of a
specific positive selection for heterozygotes among individuals in
these geographic areas, perhaps resistance to a regional infectious
pathogen, as has been elegantly demonstrated for the
hemoglobinopathies.19
ERGIC-53 is a type 1 transmembrane protein that constitutively recycles
between the ER, the ERGIC, and cis Golgi.10,14,16 The recent identification of ERGIC-53 as the gene responsible for
combined factors V and VIII deficiency provided the first direct
evidence that this protein might function as a sorting receptor in the
ER for a specific subset of secretory proteins.9 The
C-terminal sequence of ERGIC-53 (507LysLysPhePhe510) contains a
dilysine ER retrieval signal.20 Kappeler et
al21 have demonstrated by site directed mutagenesis that
the two terminal phenylalanine residues are required for exit of
ERGIC-53 from the ER. These signals also cooperate with lumenal and
transmembrane domains in the normal intracellular trafficking of
ERGIC-53. Vollenweider et al15 recently studied a
recombinant mutant ERGIC-53 in which AlaAla had replaced the
diphenylalanine motif. This mutant was prevented from recycling and
accumulated in the ER, exerting a dominant-negative effect on the
endogenous normal ERGIC-53. A selective delay in secretion of the
lysosomal protein cathepsin C was observed, consistent with the
proposed role of ERGIC-53 as a specific sorting receptor. The absence
of any other apparent disease phenotype in combined factors V and VIII
deficiency patients, outside of the bleeding disorder, suggests that
the defect in the targeting of cathepsin C or other similar proteins
may be too subtle to produce a significant functional abnormality.
All eight mutations reported here result in premature termination or
truncation removing the LysLysPhePhe motif. The most distal of these
mutations, a one base deletion in exon 13, results in a frameshift at
amino acid 508 (Table 2, family 17). This mutation substitutes
LysAsnSerPhe for the LysLysPhePhe motif, followed by 14 additional
amino acids before the next stop codon. Despite the presence of greater
than 99% (507 of 510 amino acids) of the ERGIC-53 protein, the
predicted protein, if stably folded and able to exit the ER, lacks the
critical dilysine ER retention signal20 and would likely be
constitutively secreted from the cell. In addition to deleting the KKFF
motif, all of the other identified mutations also remove the
transmembrane domain and cytoplasmic domain.22
Only one missense mutation has been identified to date in the ERGIC-53
gene in patients with combined factors V and VIII deficiency. Detected
in 4 of 7 Italian families included in the study, this single
nucleotide change results in the substitution of the initiator methionine with threonine. As the next methionine codon is not encountered until exon 2 and it is out of frame, no functional ERGIC-53
would be predicted in these patients. This same mutation was identified
by Neerman-Arbez et al18 in 2 of 8 Italian families in
their study of 35 families. The finding of only mutations that are
completely inactivating suggests that even minimal residual ERGIC-53
function might be sufficient for normal factor V and factor VIII secretion.
Although all 10 Middle Eastern and Sephardic Jewish families in our
original report had an identifiable mutation, this result was biased by
the finding of two founder mutations accounting for all patients in
this restricted population.9 In contrast, no ERGIC-53
mutation was detected in 8 of 19 families in the current study. Taken
together with our previous study of 10 Israeli families, we have failed
to find a mutation in approximately 30% (8 of 29) of the families
studied. These latter results are similar to those of Neerman-Arbez et
al,18 who were unable to detect a mutation in nine of 35 families. Mutations in portions of the ERGIC-53 gene that were not
sequenced, such as upstream regulatory regions, 3' UTR, or intron
sequences could account for these patients, although mutations of this
type are generally infrequent in other genetic disorders. However, a
hot spot for recurrent mutation, as results in the common FVIII gene
inversion in hemophilia A, could account for this
observation.23 The affected individual in family two, for
whom the mutation on only one allele was identified, is most likely
explained as a compound heterozygote with an undetected mutation in the
other allele of ERGIC-53. This patient's plasma levels of factors V
and VIII (12% FV, 14% FVIII)17 are similar to those of
other combined factors V and VIII deficiency patients, offering no
particular insight into the nature of the second, undetected mutation.
Our data for lack of linkage to ERGIC-53 in two mutation-negative
families (Fig 2) provide compelling evidence that the combined factors
V and VIII deficiency in at least a subset of these patients is due to
mutations in another gene. Consistent with this hypothesis, Neerman-Arbez et al18 observed apparently normal levels of
ERGIC-53 by Western analysis of cell extracts from EBV-immortalized B
lymphocytes in two of three families for which no ERGIC-53 mutation was
detected by single-strand conformation polymorphism and
sequence analysis. Taken together with our linkage findings, these data
strongly suggest the presence of at least one additional locus for
combined factors V and VIII deficiency. No phenotypic differences are
discernible between affected individuals for whom an ERGIC-53 mutation
has been detected and mutation-negative families or the specific subset demonstrating lack of linkage to the ERGIC-53 locus. It is likely that
the gene(s) encoded by this alternative locus also functions in the
secretory pathway for coagulation factors V and VIII, perhaps acting
directly upstream or downstream of ERGIC-53. The future identification
of this alternative gene(s) is likely to shed important light on the
biological function of this unique cargo-specific ER to Golgi transport pathway.
| |
ACKNOWLEDGMENT |
We are indebted to the families who donated samples for this study and
to Dr Tadashi Kamiya for assistance with the Japanese families.
| |
FOOTNOTES |
Submitted September 8, 1998; accepted November 13, 1998.
Supported by Grants No. HL39693 and HL57346 from the National
Institutes of Health, Bethesda, MD. D.G. and R.J.K. are
investigators of the Howard Hughes Medical Institute.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to David Ginsburg, MD, 4520 MSRB I, 1150 W
Medical Center Dr, Ann Arbor, MI 48109-0650; e-mail:
ginsburg{at}umich.edu.
| |
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Lakich D, Kazazian HH Jr, Antonarakis SE, Gitschier J:
Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A.
Nat Genet
5:236, 1993[Medline]
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