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Congenital erythropoietic porphyria: Insight into the

molecular basis of the disease
Arun Kumar Harith, Sandeep Arora1, Seema Kapoor2, Bhaskar Mukherjee3
Departments of Pathology and 1Dermatology, Base Hospital, 2Department of Human Genetics, Maulana Azad Medical College,
Department of Laboratory Sciences, Army Hospital Research and Referal, NewDelhi, India


Congenital Erythropoietic Porphyria (CEP) is a rare inborn error of metabolism charectorised by a deficiency of UROS
III enzyme, an important enzyme in the heme biosythetic pathway. It is an autosomal recessive disease and only
around 200 cases have been charectorised so far. The clinical presentation, genetic profile and the genotype-phenotype
correlation of this disease is complex, and needs to understand completely for proper diagnose of the case and instituting
specific therapy. Mutation analysis in the cases of CEP have revealed all types of mutations in the gene including
additions, substitutions, insertion and deletions in the gene. Mutations have also been charectorised in the intron-exon
junction as well as in the intron regions resulting in truncated gene product and hence a defective enzyme. Mutations in
the promoter region too have been charectorised that affect the rate of gene expression. Trans-acting mutations resulting
in a phenotype characteristic of CEP have also been recently charectorised. Various study in the molecular basis of
the disease have demonstrated that the mutations result in the production of an unstable protein that gets destroyed
rapidly resulting a critically low level of the enzyme in the biosystem. Targetting these factors which regulate the rapid
degradation of the deformed proteins have been found to improve the clinical profile of the patient and offers potential
for future therapy.

Key words: Congenital erythropoietic porphyria, erythrodontia, mutation, photodermatitis, uroporphyrinogen III synthase gene

INTRODUCTION spectrum to a mild photosensitivity on the other

end. However, most of the cases have some

C ongenital erythropoietic porphyria(CEP),

also known as Gnthers disease, is an
uncommon genetic disorder caused due to the
baseline residual enzyme activity; otherwise, they
result in death in utero. The present study reviews
the biochemical abnormalities in the disease, the
deficiency of uroporphyrinogen III cosynthase genetic defect in the disease, a genotypephenotype
enzyme deficiency, the fourth enzyme in the heme correlation, and the various therapeutic options
biosynthesis pathway. The disease is characterized available for treating this condition.
by photodermatitis, anemia, and passing of dark
colored urine. Neuropsychiatric disorders and
abdominal pain seen in some of the other kinds ADDRESS FOR CORRESPONDENCE
Dr.Arun Kumar Harith,
of porphyria is usually not seen in this condition. Department of Pathology, Base Hospital, Delhi Cantt., NewDelhi, India.
Depending on the extent of enzyme deficiency, the
clinical presentation may range from a phenotype
ranging from hydrops fetalis on one end of the This is an open access article distributed under the terms of the Creative
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others to remix, tweak, and build upon the work noncommercially, as long as
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DOI: How to cite this article: Harith AK, Arora S, Kapoor S, Mukherjee B.
10.4103/2319-7250.173147 Congenital erythropoietic porphyria: Insight into the molecular basis of the
disease. Indian J Paediatr Dermatol 2016;17:1-6.

2016 Indian Journal of Paediatric Dermatology | Published by Wolters Kluwer - Medknow 1

Harith, etal.: Genetic and molecular basis of congenital erythropoietic porphyria

BIOCHEMICAL BASIS OF CONGENITAL in the presence of light of 404nm wavelength, it forms

ERYTHROPOIETIC PORPHYRIA free radicals which then cause photodermatitis leading
the vesicle formation and scarring. Uroporphyrinogen I
Congenital erythropoietic porphyria is a rare autosomal series also tend to deposit in the teeth and sclera giving
recessive disorder. To date, only about 200cases have a reddish discoloration of the sclera and teeth known
been identified and characterized.[1] The molecular as erythrodontia[Figure3]. Uroporphyrinogen has
basis of the defect is in the enzyme uroporphyrinogen a tendency to fluorescence in ultraviolet(UV) light
III synthase(UROS)(EC that is responsible giving rise to the characteristic reddish fluorescence of
for the isomerization of hydroxymethylbilane I(formed the teeth and sclera seen in these cases when examined
by the action of cyclization of porphobilinogen(PBG) under the Woods lamp[Figure4]. The urine too shows
to uroporphyrinogen III. This isomerization at the IV similar fluorescence in UV light as uroporphyrinogen
ring of heme[Figure1] is essential as it is only the is excreted in significant amount in urine in patients
uroporphyrinogen III series which is metabolically of CEP. Anemia, usually hemolytic in nature, is
active and can be further converted to the functional commonly observed in the patients. Acombination of
heme molecule. Due to the enzyme deficiency, clinical presentation of photodermatitis, anemia, and
hydroxymethylbilane spontaneously undergoes ring erythrodontia in the presence of portwine colored urine
closure to form uroporphyrinogen I which keeps which gives bright red fluorescence in UV light makes
on accumulating. Some of it also gets converted to the diagnosis of the disease straightforward.
coproporphyrinogen I but cannot be utilized further in
heme synthesis. Accumulation of uroporphyrinogen I Heme is a potent feedback inhibitor of its
and coproporphyrinogen I is responsible for the various own biosynthesis inhibiting the first reaction,
clinical presentations of the disease including the
portwine colored urine[Figure2] and photodermatitis.
Excess of uroporphyrinogen I accumulate in the skin, and

Figure2: Portwine urine in a case of congenital erythropoietic porphyria

Figure1: Molecular difference between uroporphyrinogen 1 and
uroporphyrinogen III

Figure3: Erythrodontia Figure4: Pink fluorescence of erythrodontia in ultraviolet light

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Harith, etal.: Genetic and molecular basis of congenital erythropoietic porphyria

i.e.,combination of Glycine and Succinyl Co A to Extensive search for the cause of defect in gene
form deltaaminolevulinic acid( ALA). In cases of expression in these 11cases revealed 4 novel mutation in
CEP, as the amount of heme formed is less, there the promoter region of the erythroidspecific promoter
is no feedback inhibition of the heme synthesis. This region.[9] These included the 70 T to C transition
leads to hyperactivity of the pathway which results which resulted in altering the GATA1 binding element,
in overproduction of the toxic uroporphyrinogen 90 C to A transversion that resulted in the alteration
I series. Ineffective erythropoiesis leads to anemia of the CP2 binding element, a76 G to A transition
(usually hemolytic in nature) and splenomegaly and a86 C to A transversion. Aproband with C73R
(extramedullary hematopoiesis). At times, the and70 T to C transition reported by Solis etal.[9] had
splenomegaly may result in hypersplenism warranting a severe immune hydrops fetalis phenotype.
splenectomy. As ALA and PBG is not increased in the
case of CEP, the WatsonSchwartz tests, traditionally, The common missence mutations that have been
used as a screening test for porphyrias in many of the charectorised so far is shown in Table 1.[8] Few
developing countries is invariably negative, and many mutations have also been found which result in
cases are being underdiagnosed because of it. Urinary impaired splicing of the mRNA. These include the
porphyria studies usually done by highperformance E81D and V82F mutations. These mutations result in
liquid chromatography(HPLC) shows an increased altering the exon 4/intron 35 donor consensus. E81D
uroporphyrinogen I and coproporphyrinogen I levels resulted in 85% exon 4 skipping while V82F mutation
which clinch the diagnosis. resulted in 54% exon skipping.[10,11] Mutations in the
introns too have been identified that create alternate
splice site, e.g.,IVS2 (c.63 + 1 G>A) in which G to A
MOLECULAR BASIS OF THE DISEASE transition of the 5 donor site results in new splice site.
Deletions in the UROS gene(21delG and 148del98)
Molecular conformation of the disease is essential for
too have also been reported in cases of CEP.[12]
characterization of the disease as well as for genetic
counseling. Data on the mutations in this condition Phillips etal.[13] have described a case of CEP in which
is limited, hence sequencing of Uroporphyrinogen III there were no mutations found in the UROS gene or its
synthase (UROS gene) is commonly resorted to for promoter. However, they found an R216W mutation
proper charectorisation of the disease. The UROS in the GATA gene on the X chromosome that resulted
gene is located in the long arm of chromosome in the clinical profile of the child. The mother also
10(10q25.2q26.3) and has 10 exon spanning carried a similar mutation. The enzyme activity
over34kb in size. Aizencang etal.[2] have found that the of this mutation was approximately 21% of the
UROS gene has two different promoter, one which is a normal activity. This is probably the first transacting
housekeeping gene and has a continuous but lowlevel
expression all the cells of the body. The other promoter Table1: Common mutations in the UROS gene exons
is present in the erythroid series and is inducible. The Region Mutation Approximate enzyme activity
messenger RNA(mRNA) transcripts of the gene from (percentage of wild type activity)
the two different promoters are slightly different. Exon 2 mutations V3F <1
Y19C 1.1
As of now, approximately 39 mutations have been L4F 1.8
Exon 4 mutation C73R <1
identified[1] and wellcharacterized. These are E81D 30
mainly missense mutations, nonsense mutation, and P53L <1
frameshift mutation. The most common mutation so T62A <1
A66V 14.5
far found world over in CEP is the p.C73R mutation
A69T 1.4
which was seen in more than 20% of the cases that have Exon 5 V99A 5.6
been characterized.[3] Wiederholt etal.[4] have recently A104V 7.7
detected G236V and L237P mutation German cases of Exon 9 Q187P <1
Q188R 4.3
CEP. L237P and S47P mutations have been observed G188W 1.7
in Western Asia,[5] and there is a case report of V3F S212P <1
mutation in Vietnam.[6] Pandey etal.[7] have reported I219S 1.3
Exon 10 G225S 1.2
a p.Pro190Leu mutation in an Indian patient.
T228M <1
P248Q <1
In a series of 40 unrelated CEP cases, Desnick etal.[8] Q249X 1.1
were not able to identify both the mutations in 11cases. UROSUroporphyrinogen III synthase

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Harith, etal.: Genetic and molecular basis of congenital erythropoietic porphyria

mutation causative for CEP. In addition to the above have described a case of CEP, who had a moderate
mutation, Di Pierro etal.[14] have demonstrated 2 more phenotype. The patient was detected to have a
mutations in the X chromosome that has resulted in compound, heterozygous profile with one novel
a clinical phenotype of CEP. Asummary of mutations mutation p.P190L.
in the noncoding region of the gene resulting in CEP
is shown in Table 2.[15] While the data regarding mutations in India is
limiting, studies done in Vietnam revealed a V3F
The impact of the mutation on gene expression mutation.[6] The same mutation was seen in patients
has been studied by cloning the complementary in Japan but rare in Caucasian. The other common
DNA into Escherichia coli and checking the rate of mutations seen in the Western Asian populations
expression. It was found that most of the mutations included L237P and S47P.[5] The C73R mutation
resulted in a significant reduction of the rate of that has commonly reported in the European
enzyme expression. The most common mutation population was nor seen as frequently in the
identified, i.e.,p.C73R resulted in a residual enzyme Asian population.[6]
action of<1%. Other mutations known to produce
low enzyme activity include T62A, V3F, Y19C,
and P53L.[11] There are, however, some mutations GENOTYPEPHENOTYPE
in which the residual enzyme activity was found CORRELATIONS
to be relatively high which included V82F (~35%
Genotypephenotype correlations have been
residual activity, E81D[~30% residual activity],
attempted in the past. The first attempt was by
and A66V[~14% residual activity]).[10] Patients who
Warner etal. as early as 1992.[15] They found that
were homozygous for the pC73R mutation had a
very severe phenotype. However, patients who were patients with the A66V/C73R, T228M/C73R,
compound heterozygous for the good(A66V) and and C73R/C73R genotypes had mild, moderately
bad mutations(C73R) had a relatively milder form severe, and severe disease, respectively. C73R/C73R
of the disease.[15] homozygous mutations result in severe cases with<1%
enzyme activity.[17] ToFigueras etal.[18] studied the
genotypicphenotypic correlation in 4cases of CEP.
CONGENITAL ERYTHROPOIETIC Two cases having compound heterozygous mutations
PORPHYRIA IN ASIAN POPULATION both having one copy of the C73R mutation
(C73R/T228M and C73R/P248Q) had moderate
Reports of CEP in India are limited. Most of the
to severe disease with both hematological as well as
diagnosis was made on clinical presentation or
dermatological manifestation. However, in two cases
based on the demonstration of a characteristic
who had the similar mutation profile of P248Q/P248Q
pattern in the urine HPLC for the various
porphyrias. De etal.[16] have described a case of had different clinical presentation. One patient had
CEP without evidence of hemolysis. Pandey etal.[7] signs of features of hemolysis and photodermatitis,
whereas the other showed mild hypopigmentation and
no features of hemolysis. The residual enzyme activity
Table2: Mutations in the noncoding regions of the
UROS gene known to cause CEP in both the cases was similar. This finding clearly brings
Region Mutations characterized out that while there is a good correlation between
Promoter region 70 TC genotype and enzyme activity, the same cannot be
76 GA said for the genotypephenotype correlations.
86 CA
90 CA
660 Ins 80
672 Ins 28
Deletions 21 Del G PORPHYRIA
148 Del 98
627 Del 6 Ins 39 As of now, symptomatic therapy is being offered to
Mutations in the IVS IVS 2+1 patients with milder phenotype. Blood transfusions
are indicated in cases of severe anemia, and
IVS 9 A+4
IVSIntervening sequence; UROSUroporphyrinogen III synthase;
splenectomy may be offered to patients with features
CEPCongenital erythropoietic porphyria of hypersplenism(decrease in two or more cell lines

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Harith, etal.: Genetic and molecular basis of congenital erythropoietic porphyria

on account of moderate splenomegaly). However, approved proteasome inhibitor and found that there
bone marrow transplant is currently the best modality was marked improvement in the skin photosensitivity
of therapy that provides virtual cure to the disease.[19] as well as reduction in the porphyrin accumulation
It is hoped that the new bone marrow cells having in circulating RBCs and urine. This has been an
the normal copy of the UROS gene will populate the interesting observation and promises to open a new
marrow and produce normal erythroid precursors and modality of treatment of patients of CEP.
alleviate the clinical presentation of the disease as well
as improve the anemia. Another school of thought Financial Support and Sponsorship
includes the fact that some of the UROS gene product Nil.
may be secreted in the blood and reach target organs
to alleviate the symptoms of the patient in the similar Conflicts of Interest
lines that bone marrow transplant helps patients with There are no conflicts of interest.
lysosomal disorder. LebreuillySohyer etal.[20] studied
patients of CEP, who underwent BMT. In their study, REFERENCES
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