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Year : 2016  |  Volume : 17  |  Issue : 1  |  Page : 1-6

Congenital erythropoietic porphyria: Insight into the molecular basis of the disease

1 Department of Pathology, Base Hospital, New Delhi, India
2 Department of Dermatology, Base Hospital, New Delhi, India
3 Department of Human Genetics, Maulana Azad Medical College, New Delhi, India
4 Department of Laboratory Sciences, Army Hospital Research and Referal, New Delhi, India

Date of Web Publication4-Jan-2016

Correspondence Address:
Arun Kumar Harith
Department of Pathology, Base Hospital, Delhi Cantt., New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2319-7250.173147

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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.

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

How to cite this article:
Harith AK, Arora S, Kapoor S, Mukherjee B. Congenital erythropoietic porphyria: Insight into the molecular basis of the disease. Indian J Paediatr Dermatol 2016;17:1-6

How to cite this URL:
Harith AK, Arora S, Kapoor S, Mukherjee B. Congenital erythropoietic porphyria: Insight into the molecular basis of the disease. Indian J Paediatr Dermatol [serial online] 2016 [cited 2022 Jan 20];17:1-6. Available from: https://www.ijpd.in/text.asp?2016/17/1/1/173147

  Introduction Top

Congenital erythropoietic porphyria (CEP), also known as Günther's disease, is an uncommon genetic disorder caused due to the deficiency of uroporphyrinogen III cosynthase enzyme deficiency, the fourth enzyme in the heme biosynthesis pathway. The disease is characterized by photodermatitis, anemia, and passing of dark colored urine. Neuropsychiatric disorders and abdominal pain seen in some of the other kinds of porphyria is usually not seen in this condition. Depending on the extent of enzyme deficiency, the clinical presentation may range from a phenotype ranging from hydrops fetalis on one end of the spectrum to a mild photosensitivity on the other end. However, most of the cases have some baseline residual enzyme activity; otherwise, they result in death in utero. The present study reviews the biochemical abnormalities in the disease, the genetic defect in the disease, a genotype-phenotype correlation, and the various therapeutic options available for treating this condition.

  Biochemical Basis of Congenital Erythropoietic Porphyria Top

Congenital erythropoietic porphyria is a rare autosomal recessive disorder. To date, only about 200 cases have been identified and characterized.[1] The molecular basis of the defect is in the enzyme uroporphyrinogen III synthase (UROS) (EC that is responsible for the isomerization of hydroxymethylbilane I (formed by the action of cyclization of porphobilinogen (PBG) to uroporphyrinogen III. This isomerization at the IV ring of heme [Figure 1] is essential as it is only the uroporphyrinogen III series which is metabolically active and can be further converted to the functional heme molecule. Due to the enzyme deficiency, hydroxymethylbilane spontaneously undergoes ring closure to form uroporphyrinogen I which keeps on accumulating. Some of it also gets converted to coproporphyrinogen I but cannot be utilized further in heme synthesis. Accumulation of uroporphyrinogen I and coproporphyrinogen I is responsible for the various clinical presentations of the disease including the “port-wine” colored urine [Figure 2] and photodermatitis. Excess of uroporphyrinogen I accumulate in the skin, and in the presence of light of 404 nm wavelength, it forms free radicals which then cause photodermatitis leading the vesicle formation and scarring. Uroporphyrinogen I series also tend to deposit in the teeth and sclera giving a reddish discoloration of the sclera and teeth known as erythrodontia [Figure 3]. Uroporphyrinogen has a tendency to fluorescence in ultraviolet (UV) light giving rise to the characteristic reddish fluorescence of the teeth and sclera seen in these cases when examined under the Wood's lamp [Figure 4]. The urine too shows similar fluorescence in UV light as uroporphyrinogen is excreted in significant amount in urine in patients of CEP. Anemia, usually hemolytic in nature, is commonly observed in the patients. A combination of clinical presentation of photodermatitis, anemia, and erythrodontia in the presence of port-wine colored urine which gives bright red fluorescence in UV light makes the diagnosis of the disease straightforward.
Figure 1: Molecular difference between uroporphyrinogen 1 and uroporphyrinogen III

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Figure 2: Port-wine urine in a case of congenital erythropoietic porphyria

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Figure 3: Erythrodontia

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Figure 4: Pink fluorescence of erythrodontia in ultraviolet light

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Heme is a potent feedback inhibitor of its own biosynthesis inhibiting the first reaction, i.e., combination of Glycine and Succinyl Co A to form delta-aminolevulinic acid (δ ALA). In cases of CEP, as the amount of heme formed is less, there is no feedback inhibition of the heme synthesis. This leads to hyperactivity of the pathway which results in overproduction of the toxic uroporphyrinogen I series. Ineffective erythropoiesis leads to anemia (usually hemolytic in nature) and splenomegaly (extramedullary hematopoiesis). At times, the splenomegaly may result in hypersplenism warranting splenectomy. As δ ALA and PBG is not increased in the case of CEP, the Watson–Schwartz tests, traditionally, used as a screening test for porphyrias in many of the developing countries is invariably negative, and many cases are being underdiagnosed because of it. Urinary porphyria studies usually done by high-performance liquid chromatography (HPLC) shows an increased uroporphyrinogen I and coproporphyrinogen I levels which clinch the diagnosis.

  Molecular Basis of the Disease Top

Molecular conformation of the disease is essential for characterization of the disease as well as for genetic counseling. Data on the mutations in this condition is limited, hence sequencing of Uroporphyrinogen III synthase (UROS gene) is commonly resorted to for proper charectorisation of the disease. The UROS gene is located in the long arm of chromosome 10 (10q25.2–q26.3) and has 10 exon spanning over 34 kb in size. Aizencang et al.[2] have found that the UROS gene has two different promoter, one which is a housekeeping gene and has a continuous but low-level expression all the cells of the body. The other promoter is present in the erythroid series and is inducible. The messenger RNA (mRNA) transcripts of the gene from the two different promoters are slightly different.

As of now, approximately 39 mutations have been identified [1] and well-characterized. These are mainly missense mutations, nonsense mutation, and frameshift mutation. The most common mutation so far found world over in CEP is the p.C73R mutation which was seen in more than 20% of the cases that have been characterized.[3] Wiederholt et al.[4] have recently detected G236V and L237P mutation German cases of CEP. L237P and S47P mutations have been observed in Western Asia,[5] and there is a case report of V3F mutation in Vietnam.[6] Pandey et al.[7] have reported a p. Pro190Leu mutation in an Indian patient.

In a series of 40 unrelated CEP cases, Desnick et al.[8] were not able to identify both the mutations in 11 cases. Extensive search for the cause of defect in gene expression in these 11 cases revealed 4 novel mutation in the promoter region of the erythroid-specific promoter region.[9] These included the −70 T to C transition which resulted in altering the GATA-1 binding element, −90 C to A transversion that resulted in the alteration of the CP2 binding element, a −76 G to A transition and a −86 C to A transversion. A proband with C73R and −70 T to C transition reported by Solis et al.[9] had a severe immune hydrops fetalis phenotype.

The common missence mutations that have been charectorised so far is shown in [Table 1].[8] Few mutations have also been found which result in impaired splicing of the mRNA. These include the E81D and V82F mutations. These mutations result in altering the exon 4/intron 3 5' donor consensus. E81D resulted in 85% exon 4 skipping while V82F mutation 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 transition of the 5' donor site results in new splice site. Deletions in the UROS gene (21delG and 148del98) too have also been reported in cases of CEP.[12]
Table 1: Common mutations in the UROS gene exons

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Phillips et al.[13] have described a case of CEP in which there were no mutations found in the UROS gene or its promoter. However, they found an R216W mutation in the GATA gene on the X chromosome that resulted in the clinical profile of the child. The mother also carried a similar mutation. The enzyme activity of this mutation was approximately 21% of the normal activity. This is probably the first transacting mutation causative for CEP. In addition to the above mutation, Di Pierro et al.[14] have demonstrated 2 more mutations in the X chromosome that has resulted in a clinical phenotype of CEP. A summary of mutations in the noncoding region of the gene resulting in CEP is shown in [Table 2].[15]
Table 2: Mutations in the noncoding regions of the UROS gene known to cause CEP

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The impact of the mutation on gene expression has been studied by cloning the complementary DNA into  Escherichia More Details coli and checking the rate of expression. It was found that most of the mutations resulted in a significant reduction of the rate of enzyme expression. The most common mutation identified, i.e., p.C73R resulted in a residual enzyme action of <1%. Other mutations known to produce low enzyme activity include T62A, V3F, Y19C, and P53L.[11] There are, however, some mutations in which the residual enzyme activity was found to be relatively high which included V82F (~35% residual activity, E81D [~30% residual activity], and A66V [~14% residual activity]).[10] Patients who were homozygous for the pC73R mutation had a very severe phenotype. However, patients who were compound heterozygous for the good (A66V) and bad mutations (C73R) had a relatively milder form of the disease.[15]

  Congenital Erythropoietic Porphyria in Asian Population Top

Reports of CEP in India are limited. Most of the diagnosis was made on clinical presentation or based on the demonstration of a characteristic pattern in the urine HPLC for the various porphyrias. De et al.[16] have described a case of CEP without evidence of hemolysis. Pandey et al.[7] have described a case of CEP, who had a moderate phenotype. The patient was detected to have a compound, heterozygous profile with one novel mutation p.P190L.

While the data regarding mutations in India is limiting, studies done in Vietnam revealed a V3F mutation.[6] The same mutation was seen in patients in Japan but rare in Caucasian. The other common mutations seen in the Western Asian populations included L237P and S47P.[5] The C73R mutation that has commonly reported in the European population was nor seen as frequently in the Asian population.[6]

  Genotype – phenotype Correlations Top

Genotype-phenotype correlations have been attempted in the past. The first attempt was by Warner et al. as early as 1992.[15] They found that patients with the A66V/C73R, T228M/C73R, and C73R/C73R genotypes had mild, moderately severe, and severe disease, respectively. C73R/C73R homozygous mutations result in severe cases with <1% enzyme activity.[17] To-Figueras et al.[18] studied the genotypic-phenotypic correlation in 4 cases of CEP. Two cases having compound heterozygous mutations both having one copy of the C73R mutation (C73R/T228M and C73R/P248Q) had moderate to severe disease with both hematological as well as dermatological manifestation. However, in two cases who had the similar mutation profile of P248Q/P248Q had different clinical presentation. One patient had signs of features of hemolysis and photodermatitis, whereas the other showed mild hypopigmentation and no features of hemolysis. The residual enzyme activity in both the cases was similar. This finding clearly brings out that while there is a good correlation between genotype and enzyme activity, the same cannot be said for the genotype-phenotype correlations.

  Therapeutic Options for Cases of Congenital Erythropoietic Porphyria Top

As of now, symptomatic therapy is being offered to patients with milder phenotype. Blood transfusions are indicated in cases of severe anemia, and splenectomy may be offered to patients with features of hypersplenism (decrease in two or more cell lines on account of moderate splenomegaly). However, bone marrow transplant is currently the best modality of therapy that provides virtual cure to the disease.[19] It is hoped that the new bone marrow cells having the normal copy of the UROS gene will populate the marrow and produce normal erythroid precursors and alleviate the clinical presentation of the disease as well as improve the anemia. Another school of thought includes the fact that some of the UROS gene product may be secreted in the blood and reach target organs to alleviate the symptoms of the patient in the similar lines that bone marrow transplant helps patients with lysosomal disorder. Lebreuilly-Sohyer et al.[20] studied patients of CEP, who underwent BMT. In their study, they found that 11 of the 13 patients who underwent the therapy showed significant improvement of their clinical symptoms even after a period of 7 years, indicating that BMT is a good modality of treatment.

  Is There Any Alternatives to Bone Marrow Transplant in Congenital Erythropoietic Porphyria? Top

Recently, three-dimensional modeling of the UROS enzyme by X-ray crystallography by Mathews et al.[21] has suggested that the enzyme has two domain structure connected by two antiparallel beta-pleated ladders. The active site of the enzyme is proposed in the open cleft between the two domains. Most of the missense mutations that have been identified so far have been concentrated in the domain area and not on the active site. It is hypothesized that the mutations affect the stability of the enzyme and hence a low enzyme activity. As was discussed before, in patients who have the p.C73R mutation the residual enzyme activity in the red blood cell (RBC) was <1%. The half-life of the enzyme was ~15 min as compared to the normal half-life of 2.5 days.[22] The mutation resulted in the production of an enzyme which has some residual activity but was very labile. Fortian et al.[22] showed that the cysteine in position 73 of the UROS was not essential for the catalytic activity of the enzyme, but its mutation to arginine resulted in increase in the process of irreversible unfolding and aggregation of the enzyme, thereby reducing the half-life of the enzyme in the human system. They also demonstrated that when cell lines made of the C73R were treated with MG132, a proteasome inhibitor, the half-life of the UROS III enzyme increased and shows enzymatic activity, thereby paving a novel avenue for therapy. Blouin et al.[23] treated mice homozygous for a P248Q mutation (known to have a significant reduction in enzyme activity) with bortezomib a clinically approved proteasome inhibitor and found that there was marked improvement in the skin photosensitivity as well as reduction in the porphyrin accumulation in circulating RBCs and urine. This has been an interesting observation and promises to open a new modality of treatment of patients of CEP.

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  References Top

Ged C, Moreau-Gaudry F, Richard E, Robert-Richard E, de Verneuil H. Congenital erythropoietic porphyria: Mutation update and correlations between genotype and phenotype. Cell Mol Biol (Noisy-le-grand) 2009;55:53-60.  Back to cited text no. 1
Aizencang G, Solis C, Bishop DF, Warner C, Desnick RJ. Human uroporphyrinogen-III synthase: Genomic organization, alternative promoters, and erythroid-specific expression. Genomics 2000;70:223-31.  Back to cited text no. 2
Xu W, Astrin KH, Desnick RJ. Molecular basis of congenital erythropoietic porphyria: Mutations in the human uroporphyrinogen III synthase gene. Hum Mutat 1996;7:187-92.  Back to cited text no. 3
Wiederholt T, Poblete-Gutiérrez P, Gardlo K, Goerz G, Bolsen K, Merk HF, et al. Identification of mutations in the uroporphyrinogen III cosynthase gene in German patients with congenital erythropoietic porphyria. Physiol Res 2006;55 Suppl 2:S85-92.  Back to cited text no. 4
Moghbeli M, Maleknejad M, Arabi A, Abbaszadegan MR. Mutational analysis of uroporphyrinogen III cosynthase gene in Iranian families with congenital erythropoietic porphyria. Mol Biol Rep 2012;39:6731-5.  Back to cited text no. 5
Thien Kim DH, Kawazoe A, Bang PD, Thanh NT, Taketani S. Congenital erythropoietic porphyria: Mutation of the uroporphyrinogen III cosynthase gene in a Vietnamese patient. Case Rep Dermatol 2013;5:105-10.  Back to cited text no. 6
Pandey M, Mukherjee SB, Patra B, Kapoor S, Ged C, Aneja S, et al. Report of a novel Indian case of congenital erythropoietic porphyria and overview of therapeutic options. J Pediatr Hematol Oncol 2013;35:e167-70.  Back to cited text no. 7
Desnick RJ, Glass IA, Xu W, Solis C, Astrin KH. Molecular genetics of congenital erythropoietic porphyria. Semin Liver Dis 1998;18:77-84.  Back to cited text no. 8
Solis C, Aizencang GI, Astrin KH, Bishop DF, Desnick RJ. Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria. J Clin Invest 2001;107:753-62.  Back to cited text no. 9
Shady AA, Colby BR, Cunha LF, Astrin KH, Bishop DF, Desnick RJ. Congenital erythropoietic porphyria: Identification and expression of eight novel mutations in the uroporphyrinogen III synthase gene. Br J Haematol 2002;117:980-7.  Back to cited text no. 10
Desnick RJ, Astrin KH. Congenital erythropoietic porphyria: Advances in pathogenesis and treatment. Br J Haematol 2002;117:779-95.  Back to cited text no. 11
Xu W, Warner CA, Desnick RJ. Congenital erythropoietic porphyria: Identification and expression of 10 mutations in the uroporphyrinogen III synthase gene. J Clin Invest 1995;95:905-12.  Back to cited text no. 12
Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP. Congenital erythropoietic porphyria due to a mutation in GATA1: The first trans-acting mutation causative for a human porphyria. Blood 2007;109:2618-21.  Back to cited text no. 13
Di Pierro E, Russo R, Karakas Z, Brancaleoni V, Gambale A, Kurt I, et al. Congenital erythropoietic porphyria linked to GATA1-R216W mutation: Challenges for diagnosis. Eur J Haematol 2015;94:491-7.  Back to cited text no. 14
Warner CA, Yoo HW, Roberts AG, Desnick RJ. Congenital erythropoietic porphyria: Identification and expression of exonic mutations in the uroporphyrinogen III synthase gene. J Clin Invest 1992;89:693-700.  Back to cited text no. 15
De AK, Das K, Sil A, Joardar S. A case of congenital erythropoietic porphyria without hemolysis. Indian J Dermatol 2013;58:407.  Back to cited text no. 16
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Desnick RJ, Glass IA, Xu W, Solis C, Astrin KH. Molecular genetics of congenital erythropoietic porphyria. Semin Liver Dis 1998;18:77-84.  Back to cited text no. 17
To-Figueras J, Badenas C, Mascaró JM, Madrigal I, Merino A, Bastida P, et al. Study of the genotype-phenotype relationship in four cases of congenital erythropoietic porphyria. Blood Cells Mol Dis 2007;38:242-6.  Back to cited text no. 18
Thomas C, Ged C, Nordmann Y, de Verneuil H, Pellier I, Fischer A, et al. Correction of congenital erythropoietic porphyria by bone marrow transplantation. J Pediatr 1996;129:453-6.  Back to cited text no. 19
Lebreuilly-Sohyer I, Morice A, Acher A, Dompmartin A, Clement C, de Verneuil H, et al. Congenital erythropoeietic porphyria treated by haematopoietic stem cell allograft. Ann Dermatol Venereol 2010;137:635-9.  Back to cited text no. 20
Mathews MA, Schubert HL, Whitby FG, Alexander KJ, Schadick K, Bergonia HA, et al. Crystal structure of human uroporphyrinogen III synthase. EMBO J 2001;20:5832-9.  Back to cited text no. 21
Fortian A, González E, Castaño D, Falcon-Perez JM, Millet O. Intracellular rescue of the uroporphyrinogen III synthase activity in enzymes carrying the hotspot mutation C73R. J Biol Chem 2011;286:13127-33.  Back to cited text no. 22
Blouin JM, Duchartre Y, Costet P, Lalanne M, Ged C, Lain A, et al. Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria. Proc Natl Acad Sci U S A 2013;110:18238-43.  Back to cited text no. 23


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]

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