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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2105-2110
Inheritance in Erythropoietic Protoporphyria: A Common Wild-Type
Ferrochelatase Allelic Variant With Low Expression Accounts for
Clinical Manifestation
By
Laurent Gouya,
Herve Puy,
Jerôme Lamoril,
Vasco Da Silva,
Bernard Grandchamp,
Yves Nordmann, and
Jean-Charles Deybach
From the Centre Francais des Porphyries, INSERM U 409, Faculté
X. Bichat, Hôpital Louis Mourier, Colombes, France.
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ABSTRACT |
Erythropoietic protoporphyria (EPP) is a rare autosomal dominant
disorder of heme biosynthesis characterized by partial decrease in
ferrochelatase (FECH; EC 4.99.1.1) activity with protoporphyrin overproduction and consequent painful skin photosensitivity and rarely
liver disease. EPP is normally inherited in an autosomal dominant
pattern with low clinical penetrance; the many different mutations that
have been identified are restricted to one FECH allele, with
the other one being free of any mutations. However, clinical
manifestations of dominant EPP cannot be simply a matter of
FECH haploinsufficiency, because patients have enzyme levels that are lower than the expected 50%. From RNA analysis in one family
with dominant EPP, we recently suggested that clinical expression
required coinheritance of a normal FECH allele with low
expression and a mutant FECH allele. We now show that (1) coinheritance of a FECH gene defect and a wild-type
low-expressed allele is generally involved in the clinical expression
of EPP; (2) the low-expressed allelic variant was strongly associated with a partial 5' haplotype [ 251G IVS123T
IVS2µsatA9] that may be ancestral and was present in an
estimated 10% of a control group of Caucasian origin; and (3)
haplotyping allows the absolute risk of developing the disease to be
predicted for those inheriting FECH EPP mutations. EPP may thus
be considered as an inherited disorder that does not strictly follow
recessive or dominant rules. It may represent a model for phenotype
modulation by mild variation in expression of the wild-type allele in
autosomal dominant diseases.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
ERYTHROPOIETIC protoporphyria (EPP; MIM
#177000) is an inherited disorder of heme biosynthesis first recognized
by Magnus et al.1 EPP is caused by a partial deficiency of
ferrochelatase (FECH; EC 4.99.1.1), the terminal enzyme of the heme
biosynthetic pathway that catalyzes the insertion of ferrous iron into
protoporphyrin IX to form heme. In EPP patients, the accumulation of
free protoporphyrin due to FECH deficiency takes place principally in
the erythropoietic tissue. Clinically, an excess amount of free
protoporphyrin accumulates in the skin, causing a painful
photosensitivity in patients starting at early childhood. In less than
5% of the patients, the accumulation of protoporphyrin in the liver
leads to liver injury characterized by cholestasis and unpredictable
terminal liver failure. Mild anemia with hyperchromia and microcytosis
may occasionally be seen.2
The FECH gene contains 11 exons spans about 45 kb and is
assigned to chromosome 18q21.33-5 (GenBank no. D00726).
Heterogeneity of the molecular defects in the FECH gene has
been reported and more than 35 different mutations have been described
to date.6
The mode of inheritance of EPP is mainly autosomal dominant with
incomplete penetrance, but in two documented cases was autosomal recessive.7,8 In the dominant type of EPP, different
degrees of enzyme deficiency can be seen between patients and
asymptomatic gene carriers, ie, symptomatic patients usually have less
than 50% of the normal activity, whereas the asymptomatic ones show approximately 50% of the normal activity.9-11 This
indicates that factors in addition to the mutations are involved in the
clinical manifestations of EPP. Recently, we described one EPP family
in which clinical manifestations of the disease are modulated by the
low expression of the normal FECH allele trans to a mutant one.12 In this study, we evaluate whether this mechanism is not restricted to a single family by analyzing the expression level of
each allelic FECH gene in 4 new EPP families with dominant inheritance. Moreover, we assess that this phenomenon is generally involved in EPP using a case-control association study between 5 intragenic polymorphisms and the low-expressed FECH allele in 39 EPP nuclear families. Evaluation of the prevalence of the
low-expressed allele dramatically improves the risk prediction of overt
EPP in individuals carrying an FECH gene mutation. Finally,
this original mode of inheritance in EPP may provide insight into the
mechanism of variable penetrance in autosomal dominant diseases.
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SUBJECTS, MATERIALS, AND METHODS |
EPP pedigree analysis.
Five Caucasian EPP families (Fig 1) were
selected on typical clinical and laboratory criteria: the index cases
had a classical history of skin photosensitivity and decreased FECH
activity in lymphocytes.13 Each parent was characterized
either as a transmitter (ie, bearing the deleterious FECH
mutation with related decreased FECH enzyme activity) or as a normal
parent (ie, with normal FECH enzyme activity). Heterozygosity for at
least 1 of the 2 exonic dimorphisms (798G/C and
1520C/T) was a prerequisite for relative FECH mRNA
quantitation. Otherwise, ribonuclease protection assay was used in
selected cases for absolute quantitation.
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| Fig 1.
The coinheritance of a low-expressed FECH allelic
variant and a mutated FECH allele lead to phenotypic expression
of the disease in 5 unrelated EPP families. Solid arrows indicate the
probands. Lymphocyte FECH enzyme activity (in parentheses) is expressed
as nanomoles of Zn-mesoporphyrin per hour per milligram of protein at
37°C (control value, 5 ± 1.5; mean ± 2 SD). Specific mutations
identified in 1 FECH allele are listed in the left box.
Haplotypes were constructed from 5 polymorphic loci as listed in the
right box. Haplotypes that are associated with the low-expressed
alleles are in red, the normally expressed ones are in black (area in
white), and the mutated ones in blue. The relative amount of each
allelic FECH mRNA was determined using a fluorescent primer
extension assay. The generated peaks (one of them is indicated for each
normal parent) and their relative areas (R; see Subjects, Materials,
and Methods) are indicated in square brackets. Data are means resulting
from at least three independent experiments. Alleles that segregate
from the normal parents (I12, I21,
I32, I42, and II52) to the
probands (II12, II21,
II31, II41, II51, and
III52) carried a common 5' partial
[G-T-A9] haplotype and were associated with a lower
steady-state mRNA level. This decrease is indicated by the relative
areas (R) between allelic FECH mRNAs ranging from 1:0.5
(I12) to 1:0.74 (I42). In family 5, haplotyping
showed that the mother II52 had transmitted the
low-expressed allele to her three children. Furthermore, the daughter
(III53), a clinically normal subject, had inherited the
normal allele from her affected father and had a 50% decreased FECH
enzyme activity, in agreement with the coinheritance of two
low-expressed alleles.
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Study subjects.
(1) Thirty-nine unrelated French Caucasian nuclear EPP families
(including the above-described 5 families [77 subjects]) were investigated. The patient group consisted of 39 patients with a
documented clinical and laboratory history of EPP. The transmitter parent group consisted of 22 asymptomatic FECH gene carrier
parents. The normal parent group consisted of 16 parents with normal
FECH enzyme activity. (2) The control group consisted of 70 healthy unrelated French Caucasian subjects. The allelic distribution of the 5 polymorphisms satisfied Hardy-Weinberg equilibrium ( 2
test, P > .5). Procedures involving human subjects were
performed in accordance with the Helsinki declaration revised in 1983, and informed consent was obtained from all subjects before their
inclusion in the study.
Characterization of the specific FECH mutations.
The specific FECH gene defect in EPP family 1 has been
previously described.9 In families 2 through 5, the
specific FECH gene mutations were characterized by direct
sequencing of FECH cDNA and further confirmed at the genomic
DNA level. These four mutations were different and not previously
described ones (Fig 1). The only missense mutation, the
T790 C transition in family 4 leading to a serine
to proline substitution at position 263 (S263P), was expressed in a
prokaryotic system (pGEX-2T vector; Pharmacia Biotech, Uppsala, Sweden)
using site-directed mutagenesis (Transformer site-directed mutagenesis
kit; Clontech Laboratories, Palo Alto, CA) and showed a residual FECH
enzyme activity at 0.5% ± 0.02% (mean ± 2 SD) as compared
with 100% for the normal cDNA.
Genotyping for 5 intragenic polymorphisms.
Five intragenic polymorphisms distributed over the FECH gene
were studied. DNA was prepared from lymphoblastoid cell line as
previously described.12 251A/G in the
5' promoter region, IVS123C/T,14,15 close to the branch
point of intron 1, a dinucleotide repeat in intron 2 called
IVS2µsat:Ann: 1 10, 798G/C in
exon 7, and 1520C/T in the 3' UTR. Genotyping for
251A/G, 1520C/T, and IVS2µsat:An was performed
as previously described.12,16 The
IVS123C/T dimorphism was screened as follows. The
intron 1/exon 1 junction was amplified by polymerase chain reaction
(PCR) and then digested by the restriction enzyme Cac8I
according to the manufacturer's instructions (New England Biolabs,
Beverly, MA). The 23T allelic fragment is specifically
cut by this enzyme. The 798G/C dimorphism in exon 7 was
screened as follows. After PCR amplification, exon 7 is digested with
Nla III restriction enzyme (New England Biolabs) and the 798C
allelic fragment is cut into two parts.
Relative quantitation of FECH mRNA by fluorescent primer extension
assay.
Total RNA isolated from a lymphoblastoid cell line17 was
reverse transcribed as described.12 Two regions of
FECH cDNA were amplified spanning nucleotides +693 to +1273 and
+1328 to +1568. Primer extension assay was performed as previously
described.12,18,19 Two fluorescent primers were used: 798F,
5'-flTTTTCTGCTCACTCACTG-3'; and 1520F,
5'-flCCTTTAATAAATGAGTTAA, respectively, located close to
polymorphic loci 798G/C (+693/+1273 amplimer) and
1520C/T (+1328/+1568 amplimer). Extended primers were separated
on a Alf DNA automated sequencer (Pharmacia Biotech) and peak areas
were calculated using the Fragment Manager program (Pharmacia Biotech).
Results are expressed as the peak area ratios (R) of the corresponding
allelic FECH mRNAs: R798 = (peak area of
FECH mRNA bearing a 798G allele)/(peak area of
FECH mRNA bearing a 798C allele); and R1520 = (peak area of FECH mRNA bearing a 1520C allele)/(peak
area of FECH mRNA bearing a 1520T allele).
Ribonuclease protection assay.
In some cases, FECH mRNA was quantified by ribonuclease
protection assay as previously described.12 In family 5, the specific gene mutation (IVS9 1 g a)
leads to exon 10 skipping, allowing a FECH probe that include
exon 10 to be used for quantifying the normal allele independently to
the mutated one. Two RNA antisense probes were synthesized: a
FECH probe containing the last 414 FECH cDNA
nucleotides cohybridized with an L ferritin control probe
containing the first 125 L ferritin cDNA nucleotides to correct
experimental variability. Results are expressed as the ratio (R) of the
normal FECH mRNA to the L ferritin mRNA.
Statistical analysis.
Genotype and allele distribution was analyzed using the
2 test. Odds ratio and 95% confidence intervals (CI)
were calculated.20 The high prevalence of the
IVS2µsatA9 allele resulted in a high percentage of
homozygotes. The data were then collapsed and analyzed in 2 × 2 format using 2 statistics. Linkage disequilibrium (D)
studies were performed according to Thomson et al.21
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RESULTS AND DISCUSSION |
Five EPP families with dominant inheritance were studied (ie, partial
decrease in FECH enzyme activity associated with a specific FECH mutation in one of the FECH alleles in the proband
and in one parent; Fig 1). In these 5 families, 5 different
FECH mutations were found, and 4 were newly described (Fig 1).
Allelic segregation patterns and relative RNA quantitation showed that
clinical expression in EPP patients in these families always resulted
from the coinheritance of a wild-type low-expressed allele with a
mutant one. Haplotyping using 5 intragenic polymorphisms spread over
the 45 kb of the FECH gene from the 5' promoter region to
the 3' untranslated region (3' UTR) (251A/G,
IVS123C/T, IVS2µsat:An, 798G/C, and
1520C/T) showed that this low-expression variant was (1)
systematically transmitted from the normal parent to the patient and
(2) associated with two haplotypes sharing the same 5' part
[G-T-A9] (Fig 1). Not one of these sequence variations was by
itself directly involved in the low expression, as attested by allelic
segregation in family 1. The normal parent I12, although
homozygous for the 5' partial [G-T-A9] haplotype,
transmitted a low-expressed allele to the proband (II12)
but a normally expressed allele to another sibling (II11),
an asymptomatic carrier of an FECH mutation (Fig 1). Tugores et
al22 described many regulatory elements of interest in the promoter region of the FECH gene. Nevertheless, they do not
appear to be involved in low-expression mechanism, because no sequence variation has been found in more than 1 kb of the proximal promoter. Recently, Scott et al23 reported a new region
2 kb upstream from the transcription start site that may contribute to
a high level of erythroid specific expression of FECH gene by
maintaining an active chromatine configuration. One might hypothesize
that mutations in this region bearing erythroid-specific regulatory elements could be involved in the FECH gene low expression.
Such a mechanism clearly needs to be evaluated in further studies on FECH gene expression. On the other hand, sequencing the coding regions as well as part of intron 1 and 3' UTR to search for
mutations that might decrease FECH mRNA steady-state level
failed to detect any other sequence variations.
These observations based on a limited number of EPP families were
extended by a case-control association study in 39 EPP nuclear families
in which the distribution of the 5 FECH intragenic
polymorphisms was analyzed. The subjects were divided into 3 groups:
(1) the patient group, (2) the transmitter parent group (ie,
asymptomatic parents bearing a specific FECH mutation), and (3)
the normal parent group. The most striking finding was that the patient
group and the normal parent group exhibited a similar increase in the frequency of a specific set of alleles (G, T, A9, T;
Table 1), one of which has previously been
reported to be overrepresented in EPP patients,14 whereas
none of them was associated with the transmitter parent (FECH
mutation carriers) group. It is thus surprising that such a strong
association exists between FECH polymorphisms and overt EPP
patients but not with asymptomatic carriers of FECH mutations.
This is in agreement with the vast heterogeneity in FECH
mutations (38 different ones reported to date6). It also
assesses that the normal parents transmit to the overt EPP siblings a
common but specific wild-type FECH allele. In accordance with
their physical proximity, we found evidence for linkage disequilibrium
between 251G and IVS123T,
IVS2µsatA9, and 1520T polymorphisms
(Table 2). This strongly indicates that the
low-expressed allele is associated with a major [G-T-A9-T] haplotype.
The invariable presence in the 7 EPP patients (Fig 1) of a wild-type
low-expressed allelic variant with the same 5' partial [G-T-A9] haplotype implies that this allele should appear
with a fairly high frequency in the general population. This was tested in a control group of 70 unrelated normal subjects of whom 39 were
heterozygous for one of the exonic dimorphisms 798G/C or 1520C/T and thus available for RNA quantitation. The bimodal
distribution of the quantitation data allowed isolation of a subgroup
of 9 subjects with FECH allelic mRNA ratios of 0.7 or
less. Eight of the nine low-expressed
alleles were associated with the same 5' partial
[G-T-A9] haplotype (Fig 2). Haplotypic variations for the
3' polymorphisms indicate that recombination in this part of the
gene does not affect expression, suggesting that the mutation(s) causing low expression lies in the 5' part of an FECH
gene with an ancestral [G-T-A9] haplotype. The frequency of
the low-expressed FECH allele in the control population could
be estimated from 6.5% (9/140, assuming that none of the 31 unexplored
subjects had a low-expressed allelic variant) to 11.5% (9/78, assuming that this ratio reflects the real frequency of the allelic variant in
the whole group). At such a high heterozygote frequency, about 1% of
the population should be homozygote. Such a homozygote was suspected on
genotypic analysis in EPP family 5 (subject III53; Fig 1).
mRNA relative quantitations showed that the mother II52 had
transmitted a low-expressed allele to this subject (Fig 1). A
ribonuclease protection assay was used for absolute quantitation of the
nonmutant FECH allele in this family (see Subjects, Materials, and Methods). Compared with the control subject (R = 8.3), FECH mRNA level was 75% lower in the symptomatic father II51 (R = 2.6; 1 deleterious allele and 1 low-expressed one) and 50% lower in the daughter III53 (R = 4.1); as expected, these data were
strongly correlated with a similar decrease in FECH enzyme activities
(Fig 1). Because no de novo FECH mutation could be found by
sequencing (not shown), this gives evidence for the presence in subject
III53 of two coinherited low-expressed alleles. This
subject has no clinical or biochemical signs of EPP but would have been
misdiagnosed as a gene carrier in a family study based solely on FECH
enzyme measurement.
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| Fig 2.
Distribution of the FECH allelic mRNA ratios in
39 Caucasian controls. Data are presented as histogram of the observed
distribution at 0.1 intervals and a polynomial tendency curve.
According to the bimodal distribution, the 39 subjects could be
separated into a main subgroup of 30 with equally expressed
FECH alleles (mean, 1.02; 95% CI, 0.96 to 1.08) and a smaller
group of 9 with a marked disequilibrium in their relative FECH
mRNA allelic representation (mean, 0.59; 95% CI, 0.58 to 0.60).
Haplotypes for the 9 low-expressed alleles were [G-T-A9-T] in
6 cases, [G-T-A9-C] in 2, and [A-C-A9-T] in 1.
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These data lead to a number of conclusions. First, that the low
expression of a wild-type allelic variant trans to a mutated FECH allele is generally required for clinical expression of
EPP. It is likely that when FECH enzyme activity falls below a critical threshold, the accumulation of protoporphyrin will exceed hepatic clearance capacity and lead to clinically manifest EPP. In fact, asymptomatic EPP carriers often have normal or slightly elevated protoporphyrin levels in erythrocytes2 and higher FECH
enzyme activity than overt EPP patients.10,11 Second, that
the low-expressed alleles are inherited from the normal parent and most
if not all of these alleles probably originate from a mutational
event(s) that occurred in a common ancestral [G-T-A9]
haplotype. However, the mechanism of low expression remains unknown.
Third, that the frequency of the low-expressed allele in the general
Caucasian population is of the order of 6.5% to 11.5%. Finally, our
results have important implications for genetic counseling in EPP. From the frequency of low-expressed alleles bearing specific 5'
haplotypes (251G IVS123T or
251A IVS123C) in the 39 individuals
studied, it can be estimated that the absolute risk that a carrier of
an FECH mutation will develop symptomatic EPP when bearing the
[251G IVS123T] haplotype trans to a
mutant one is close to 60%. More importantly, the risk decreases to
less than 2% if this haplotype is [251A
IVS123C], which, fortunately, is the most frequent one
(75% of [251A IVS123C] homozygotes in the
control group). Indeed, in these estimations we assume that the
penetrance of EPP symptoms in subjects having a genotype with a mutant
FECH allele associated with a low-expressed allele is almost
100% at 15 years of age. As compared with the empirical risk of EPP
symptoms proposed by Went and Klasen,24 our results provide
a dramatic improvement in risk prediction for an unborn child in an EPP
family based on parental haplotype study.
Although autosomal recessive inheritance has been documented in 2 cases,7,8 EPP has long been considered as an autosomal dominant disorder with incomplete penetrance. Molecular analysis supports this notion, because only a single mutation is identified in
patients in one of the FECH alleles. However, EPP patients exhibit a lower FECH enzyme activity than the 50% expected in autosomal dominant disease with haploinsufficiency. This strongly suggests a more complex mode of inheritance. Went and
Klasen24 proposed a triallelic system in which, in addition
to the usual deleterious and normal FECH alleles, they advanced
the presence of a third FECH allele that, in association to the
deleterious one, leads to the EPP clinical outcome. This third allele
was also expected to present a fairly high frequency in general
population. This triallelic system accounted for the autosomal
recessive appearance of the EPP family pedigrees and the dominant
transmission of biochemical characters. We provide here strong
molecular evidence that the third allele is a low-expressed wild-type
allele insufficient by itself, or in the homozygous state, to cause
overt EPP yet sufficiently frequent in the population to cause manifest
disease through coinheritance with a rare FECH EPP mutation.
This allele appears thus more as a triggering factor than a deleterious
allele. We therefore prefer still to consider EPP as an autosomal
dominant disorder than a recessive one (strictly speaking 2 deleterious alleles). However, the mendelian rules of recessive and dominant inheritance of genetic traits may appear somewhat meaningless in EPP. A
situation similar to that described here has been documented in
hereditary elliptocytosis (HE).25,26 Finally, such a
mechanism in which mild variations of the wild-type gene expression
level may account for variable penetrance or clinical expression in many dominantly inherited disorders such as Hirschsprung
disease,27 campomelic dysplasia, or basal cell nevus
syndrome.28
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ACKNOWLEDGMENT |
Special thanks to Prof G.H. Elder (Department of Medical Biochemistry,
University of Wales College of Medicine, Cardiff, UK) and Dr X. Schneider-Yin (Stadspital Triemli, Zurich, Switzerland) for helpful
discussions and critical review of the manuscript.
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FOOTNOTES |
Submitted September 8, 1998; accepted November 3, 1998.
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 Jean-Charles Deybach, MD, Centre Francais
des Porphyries, INSERM U 409, Faculté X. Bichat, Hôpital
Louis Mourier, 92701 Colombes Cedex, France; e-mail:
jc.deybach{at}wanadoo.fr.
| |
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