Study of the genotype–phenotype relationship in four cases of congenital erythropoietic porphyria
Introduction
Congenital erythropoietic porphyria (CEP) also known as Günther disease, is an inborn error of metabolism that results from a deficient activity of the fourth enzyme of the haem biosynthetic pathway, uroporphyrinogen III synthase (URO-synthase; EC 4.2.1.75). The disease is rare, with about 150 cases, having been reported to date in the literature, and is transmitted as an autosomal recessive trait [1]. Due to the enzyme deficiency, the affected homozygotes present an excessive nonenzymatic conversion of the linear tetrapyrrole hydroxymethylbilane (HMB) to the nonphysiologic uroporphyrinogen I (URO I). This is further metabolized to coproporphyrinogen I (COPRO I) that cannot be metabolized to haem. Consequently, both isomers accumulate in bone marrow erythroid precursors, undergo auto-oxidation to the corresponding porphyrins and induce erythrocyte damage. In addition, both porphyrins are distributed throughout the body, with substantial amounts accumulating in the bones and skin and a large fraction being excreted by feces and urine. The clinical manifestations of CEP are heterogeneous and range from hydrops fetalis due to severe hemolytic anemia in utero, to milder forms with only cutaneous lesions in adult life. Some patients are transfusion-dependent throughout life. Some present severe scarring and deformities due to the highly photocatalytic and cytotoxic capacity of the accumulated uroporphyrins in the skin. Other typical symptoms of CEP include secondary hypersplenism and erythrodontia [2].
The URO-synthase gene has been assigned to the narrow chromosomal region 10q25.3→q26.3. To date, and according to the Human Gene Mutation Database (Cardiff), 36 mutations causing CEP have been reported in the 10 exons of the gene, including missense, nonsense mutations, deletions and insertions [3]. Mutations in the erythroid-specific promoter region have also been described [4]. Expression of the missense mutations in Escherichia coli has revealed that some alleles encode enzymes with very low, if any, residual activity, while others retain substantial amounts of functionality [5].The degree of enzymatic residual activity in vivo may determine the amount of porphyrins accumulated and consequently may correlate with the severity of the disease [6]. However, although most known CEP mutations have been tested in prokaryotes, some allelic combinations have never been reported and consequently, the final clinical effect of these genotypes is unknown.
We report a clinical, biochemical and molecular study of four Spanish CEP cases including two homozygous cases with an allelic combination never reported before. In all the patients we have studied the relationship between the genotype and the phenotypic expression of the disease.
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Patients
We studied 3 adult patients: a woman aged 32 years (patient C); a woman aged 28 years (patient A); a man aged 45 years (patient D) and a girl of ten months of age (B). All were Spanish patients diagnosed with CEP during childhood and clinically followed in the Dermatology Unit of Hospital Clinic of Barcelona (Spain). The four patients belonged to non-related Spanish families; in one case (C) there was consanguinity while in the other three there was apparently not. At the onset of the disease
Results
The essential clinical data of the four CEP patients are shown in Table 1. Cutaneous involvement was severe in patients A and C with scarring and mutilations being very mild in patient D with only hyperpigmentation but no scarring or mutilations. The essential hematological parameters of these patients are shown in Table 2. Three patients presented hematological involvement with anemia, splenomegaly and signs of hemolysis but patient D presented normal hematological values in peripheral blood
Discussion
Two of the patients here reported harbor a C73R missense mutation in exon 4 of the URO-synthase gene. This mutation is the most common in CEP patients being found in about 1/3 of the alleles studied according to different reports [1]. Our results on four Spanish CEP patients seem to confirm these previous observations. Haplotype analyses have shown that the high frequency of C73R is due to independent mutational events and not the result of a founder effect [18]. The T228 mutation found in
Acknowledgments
The study was supported by grants from the Spanish “Fondo de Investigación Sanitaria” (03/0489). We appreciate the participation of the family members in this study. We appreciate the technical assistance of Maria Sala and the collaboration of Dr M Morey (Hospital Son Dureta).
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2013, Actas Dermo-SifiliograficasCitation Excerpt :However, the majority of the remaining mutations have been found in single families or, at most, just a few families of CEP patients. In addition, although it is generally accepted that the degree of residual in vivo activity of the UROS enzyme determines the severity of the disease, there have been reports of patients with the same mutations in the UROS gene with very different phenotypes.44 As a result, it is very hard to establish a genotype-phenotype correlation in CEP.
ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria
2011, BloodCitation Excerpt :The significance of differences between quantitative variables and proportions was assessed with the Mann-Whitney U test and the Student t test. Patient 1 had already been reported by To-Figueras et al,10 whereas patients 2-4 are now described. In all patients, separation and quantification of porphyrins by HPLC showed a typical CEP pattern for urine and erythrocytes with accumulation of porphyrin series I isomers.
Intracellular rescue of the uroporphyrinogen III synthase activity in enzymes carrying the hotspot mutation C73R
2011, Journal of Biological ChemistryCitation Excerpt :Because porphyrins mostly accumulate in the marrow, current treatment has focused on marrow suppression and bone marrow transplantation with an uneven degree of success (5, 6). At the molecular level, the severity of the disease is dependent ultimately on the nature of the inborn error (7–9). Genetic analyses of >110 CEP patients have identified ∼25 missense mutations as well as four defects in the promoter region (10, 11).