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Identification of a novel UROS mutation in a Chinese patient affected by congenital erythropoietic porphyria
Blood Cells, Molecules and Diseases 52 (2014) 57–58
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Letter to the Editor Identification of a novel UROS mutation in a Chinese patient affected by congenital erythropoietic porphyria To the editor: Porphyrias are a group of rare inherited or acquired disorders caused by deficiencies in the activities of the enzymes involved in heme biosynthesis pathway. These molecular defects lead to specific accumulation of different precursors for heme biosynthesis [1]. Congenital erythropoietic porphyria (CEP), the most serious and frequent type of rare recessive porphyrias, is characterized by cutaneous photosensitivity and massive porphyrinuria. This disorder results from a pronounced deficiency of uroporphyrinogen III synthase (UROS) enzymatic activity, causing specific overproduction and excretion of the non-physiological and pathogenic isomer I of uroporphyrin and coproporphyrin, which causes photosensitization [2]. Clinical presentations of CEP include cutaneous photosensitivity and chronic hemolysis. Most patients have severe photosensitivity since childhood, leading to bullae, scarring, and eventually disfigurement of the light-exposed parts of the body, such as the hands, face, ears and scalp [1,3]. Long term exposure to sunlight may lead to scaring in the skin, deformities, and loss of fingernails and digits. Red urine is usually noticed firstly in the patients affected by CEP because of the large amount of porphyrin in the urine. Almost all the patients with CEP show erythrodontia, osteodystrophia, combined osteolysis and osteoporosis and hypercellular bone marrow [1]. Anemia is another feature of this disease. To date, over 200 cases of CEP have been reported in PubMed Central (PMC), among which mostly are Caucasian patients. Molecular studies of the UROS gene in these patients have identified 47 mutations from different families all over the world (according to the Human Gene Mutation Database, HGMD®, http://www.hgmd.org), including 3 mutations in Asian population [4–6]. However, there are very few detailed reports of CEP in Chinese people. Herein we report a novel pathogenic mutation in UROS in a Chinese CEP patient. To the best of our knowledge, it's the first description of CEP mutations in Chinese population. The patient was a 20-year-old male from a consanguineous family. He had suffered from painful photosensitivity for 14 years, indicating the possibility of erythropoietic protoporphyria, X-linked dominant protoporphyria, congenital erythropoietic porphyria and hepatoerythropoietic porphyria. Other clinical presentations include bullae, scarring, and eventually disfigurement of the light-exposed parts of his body. He has developed red-colored urine and jaundice for six years. The level of Hb (140 g/L, normal range 120–160 g/L) and MCH (29 pg, normal range 27–32 pg) was normal. The possibility of hepatoerythropoietic porphyria (HEP) was excluded by the normal level of zinc protoporphyrin (under 3 μg/g Hb). TBil (20.4 μmol/L, normal range 5.1–22.2 μmol/L), DBil (6.5 μmol/L, normal range 0–8.6 μmol/L) and LDH (242 U/L, normal range 96–240 U/L) didn't
1079-9796/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bcmd.2013.07.012
show the haemolysis. A diagnosis of CEP was confirmed by the plasma fluorescence emission spectroscopy test, which showed an emission peak at 618 nm. We then sequenced the UROS gene of the patient with 5′ and 3′ primers targeting each of the nine exons and flanking splice junctions of UROS, and identified a novel mutation (Fig. S1). It is a homozygous c.416TNG transversion located in exon 7 of UROS, leading to a L139R substitution at the terminal of the β6 chain of the protein. L139 is highly conserved among the UROS protein from five mammalian species (Fig. S2). According to a previous work, we speculate that this mutation could disrupt the packing of the adjacent conserved residue L140 because of the larger size and positive charge of arginine and the following change of the biochemical properties of β6 chain [7]. The current study is the first UROS missense mutation identified in Chinese CEP patients, and would be helpful for genetic counseling and prenatal diagnosis of related diseases. This study may contribute to the UROS mutation mapping, as well as the analysis of the genotype– phenotype correlation in erythropoietic porphyria. Conflict of interest The authors have no conflict of interest. Acknowledgments This work was supported by grants from MOST 973 program (2012CB934004), NSFC (10979011; 30900278; 81070401) and National Public Health Grand Research Foundation (No. 201202017). GN acknowledges the support of Chinese Academy of Sciences, Hundred Talents Program. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.bcmd.2013.07.012. References [1] H. Puy, L. Gouya, J.C. Deybach, Porphyrias, Lancet 375 (2010) 924–937. [2] W. Xu, K.H. Astrin, R.J. Desnick, Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene, Hum. Mutat. 7 (1996) 187–192. [3] C. Fritsch, K. Bolsen, T. Ruzicka, G. Goerz, Congenital erythropoietic porphyria, J. Am. Acad. Dermatol. 36 (1997) 594–610. [4] N. Takamura, I. Hombrados, K. Tanigawa, et al., Novel point mutation in the uroporphyrinogen III synthase gene causes congenital erythropoietic porphyria of a Japanese family, Am. J. Med. Genet. 70 (1997) 299–302. [5] T. Rogounovitch, N. Takamura, I. Hombrados, et al., Congenital erythropoietic porphyria: a novel homozygous mutation in a Japanese patient, J. Invest. Dermatol. 115 (2000) 1156. [6] K. Tanigawa, M. Bensidhoum, N. Takamura, et al., A novel point mutation in congenital erythropoietic porphyria in two members of Japanese family, Hum. Genet. 97 (1996) 557–560.
58
Letter to the Editor
[7] M.A. Mathews, H.L. Schubert, F.G. Whitby, et al., Crystal structure of human uroporphyrinogen III synthase, EMBO J. 20 (2001) 5832–5839.
Shanshan Guo1 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing 100190, China E-mail address: [email protected]. Lu Wang1 Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100032, China Xiaojing Li Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China Guangjun Nie CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology,
Nanosafety, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing 100190, China Mianyang Li Clinical laboratory, Chinese PLA General Hospital, Beijing, 100853, China Corresponding author. E-mail address: [email protected]. Bing Han Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China Corresponding author. E-mail address: [email protected]. 1
Shanshan Guo and Lu Wang contributed equally to this work.
7 March 2013
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Letter to the Editor Identification of a novel UROS mutation in a Chinese patient affected by congenital erythropoietic porphyria To the editor: Porphyrias are a group of rare inherited or acquired disorders caused by deficiencies in the activities of the enzymes involved in heme biosynthesis pathway. These molecular defects lead to specific accumulation of different precursors for heme biosynthesis [1]. Congenital erythropoietic porphyria (CEP), the most serious and frequent type of rare recessive porphyrias, is characterized by cutaneous photosensitivity and massive porphyrinuria. This disorder results from a pronounced deficiency of uroporphyrinogen III synthase (UROS) enzymatic activity, causing specific overproduction and excretion of the non-physiological and pathogenic isomer I of uroporphyrin and coproporphyrin, which causes photosensitization [2]. Clinical presentations of CEP include cutaneous photosensitivity and chronic hemolysis. Most patients have severe photosensitivity since childhood, leading to bullae, scarring, and eventually disfigurement of the light-exposed parts of the body, such as the hands, face, ears and scalp [1,3]. Long term exposure to sunlight may lead to scaring in the skin, deformities, and loss of fingernails and digits. Red urine is usually noticed firstly in the patients affected by CEP because of the large amount of porphyrin in the urine. Almost all the patients with CEP show erythrodontia, osteodystrophia, combined osteolysis and osteoporosis and hypercellular bone marrow [1]. Anemia is another feature of this disease. To date, over 200 cases of CEP have been reported in PubMed Central (PMC), among which mostly are Caucasian patients. Molecular studies of the UROS gene in these patients have identified 47 mutations from different families all over the world (according to the Human Gene Mutation Database, HGMD®, http://www.hgmd.org), including 3 mutations in Asian population [4–6]. However, there are very few detailed reports of CEP in Chinese people. Herein we report a novel pathogenic mutation in UROS in a Chinese CEP patient. To the best of our knowledge, it's the first description of CEP mutations in Chinese population. The patient was a 20-year-old male from a consanguineous family. He had suffered from painful photosensitivity for 14 years, indicating the possibility of erythropoietic protoporphyria, X-linked dominant protoporphyria, congenital erythropoietic porphyria and hepatoerythropoietic porphyria. Other clinical presentations include bullae, scarring, and eventually disfigurement of the light-exposed parts of his body. He has developed red-colored urine and jaundice for six years. The level of Hb (140 g/L, normal range 120–160 g/L) and MCH (29 pg, normal range 27–32 pg) was normal. The possibility of hepatoerythropoietic porphyria (HEP) was excluded by the normal level of zinc protoporphyrin (under 3 μg/g Hb). TBil (20.4 μmol/L, normal range 5.1–22.2 μmol/L), DBil (6.5 μmol/L, normal range 0–8.6 μmol/L) and LDH (242 U/L, normal range 96–240 U/L) didn't
1079-9796/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bcmd.2013.07.012
show the haemolysis. A diagnosis of CEP was confirmed by the plasma fluorescence emission spectroscopy test, which showed an emission peak at 618 nm. We then sequenced the UROS gene of the patient with 5′ and 3′ primers targeting each of the nine exons and flanking splice junctions of UROS, and identified a novel mutation (Fig. S1). It is a homozygous c.416TNG transversion located in exon 7 of UROS, leading to a L139R substitution at the terminal of the β6 chain of the protein. L139 is highly conserved among the UROS protein from five mammalian species (Fig. S2). According to a previous work, we speculate that this mutation could disrupt the packing of the adjacent conserved residue L140 because of the larger size and positive charge of arginine and the following change of the biochemical properties of β6 chain [7]. The current study is the first UROS missense mutation identified in Chinese CEP patients, and would be helpful for genetic counseling and prenatal diagnosis of related diseases. This study may contribute to the UROS mutation mapping, as well as the analysis of the genotype– phenotype correlation in erythropoietic porphyria. Conflict of interest The authors have no conflict of interest. Acknowledgments This work was supported by grants from MOST 973 program (2012CB934004), NSFC (10979011; 30900278; 81070401) and National Public Health Grand Research Foundation (No. 201202017). GN acknowledges the support of Chinese Academy of Sciences, Hundred Talents Program. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.bcmd.2013.07.012. References [1] H. Puy, L. Gouya, J.C. Deybach, Porphyrias, Lancet 375 (2010) 924–937. [2] W. Xu, K.H. Astrin, R.J. Desnick, Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene, Hum. Mutat. 7 (1996) 187–192. [3] C. Fritsch, K. Bolsen, T. Ruzicka, G. Goerz, Congenital erythropoietic porphyria, J. Am. Acad. Dermatol. 36 (1997) 594–610. [4] N. Takamura, I. Hombrados, K. Tanigawa, et al., Novel point mutation in the uroporphyrinogen III synthase gene causes congenital erythropoietic porphyria of a Japanese family, Am. J. Med. Genet. 70 (1997) 299–302. [5] T. Rogounovitch, N. Takamura, I. Hombrados, et al., Congenital erythropoietic porphyria: a novel homozygous mutation in a Japanese patient, J. Invest. Dermatol. 115 (2000) 1156. [6] K. Tanigawa, M. Bensidhoum, N. Takamura, et al., A novel point mutation in congenital erythropoietic porphyria in two members of Japanese family, Hum. Genet. 97 (1996) 557–560.
58
Letter to the Editor
[7] M.A. Mathews, H.L. Schubert, F.G. Whitby, et al., Crystal structure of human uroporphyrinogen III synthase, EMBO J. 20 (2001) 5832–5839.
Shanshan Guo1 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing 100190, China E-mail address: [email protected]. Lu Wang1 Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100032, China Xiaojing Li Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China Guangjun Nie CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology,
Nanosafety, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing 100190, China Mianyang Li Clinical laboratory, Chinese PLA General Hospital, Beijing, 100853, China Corresponding author. E-mail address: [email protected]. Bing Han Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China Corresponding author. E-mail address: [email protected]. 1
Shanshan Guo and Lu Wang contributed equally to this work.
7 March 2013