Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Nov;63(5):1363–1375. doi: 10.1086/302119

Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles.

M Mendez 1, L Sorkin 1, M V Rossetti 1, K H Astrin 1, A M del C Batlle 1, V E Parera 1, G Aizencang 1, R J Desnick 1
PMCID: PMC1377546  PMID: 9792863

Abstract

Familial porphyria cutanea tarda (f-PCT) results from the half-normal activity of uroporphyrinogen decarboxylase (URO-D). Heterozygotes for this autosomal dominant trait are predisposed to photosensitive cutaneous lesions by various ecogenic factors, including iron overload and alcohol abuse. The 3.6-kb URO-D gene was completely sequenced, and a long-range PCR method was developed to amplify the entire gene for mutation analysis. Four missense mutations (M165R, L195F, N304K, and R332H), a microinsertion (g10insA), a deletion (g645Delta1053), and a novel exonic splicing defect (E314E) were identified. Expression of the L195F, N304K, and R332H polypeptides revealed significant residual activity, whereas reverse transcription-PCR and sequencing demonstrated that the E314E lesion caused abnormal splicing and exon 9 skipping. Haplotyping indicated that three of the four families with the g10insA mutation were unrelated, indicating that these microinsertions resulted from independent mutational events. Screening of nine f-PCT probands revealed that 44% were heterozygous or homozygous for the common hemochromatosis mutations, which suggests that iron overload may predispose to clinical expression. However, there was no clear correlation between f-PCT disease severity and the URO-D and/or hemochromatosis genotypes. These studies doubled the number of known f-PCT mutations, demonstrated that marked genetic heterogeneity underlies f-PCT, and permitted presymptomatic molecular diagnosis and counseling in these families to enable family members to avoid disease-precipitating factors.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson M. A., Gusella J. F. Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro. 1984 Nov;20(11):856–858. doi: 10.1007/BF02619631. [DOI] [PubMed] [Google Scholar]
  2. Chen C. H., Astrin K. H., Lee G., Anderson K. E., Desnick R. J. Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene. An initiation codon missense mutation in the housekeeping transcript causes "variant acute intermittent porphyria" with normal expression of the erythroid-specific enzyme. J Clin Invest. 1994 Nov;94(5):1927–1937. doi: 10.1172/JCI117543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cooper D. N., Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet. 1988 Feb;78(2):151–155. doi: 10.1007/BF00278187. [DOI] [PubMed] [Google Scholar]
  4. DeCastro M., Sánchez J., Herrera J. F., Cháves A., Durán R., García-Buey L., García-Monzón C., Sequí J., Moreno-Otero R. Hepatitis C virus antibodies and liver disease in patients with porphyria cutanea tarda. Hepatology. 1993 Apr;17(4):551–557. doi: 10.1002/hep.1840170405. [DOI] [PubMed] [Google Scholar]
  5. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  6. Dubart A., Mattei M. G., Raich N., Beaupain D., Romeo P. H., Mattei J. F., Goossens M. Assignment of human uroporphyrinogen decarboxylase (URO-D) to the p34 band of chromosome 1. Hum Genet. 1986 Jul;73(3):277–279. doi: 10.1007/BF00401245. [DOI] [PubMed] [Google Scholar]
  7. Elder G. H., Lee G. B., Tovey J. A. Decreased activity of hepatic uroporphyrinogen decarboxylase in sporadic porphyria cutanea tarda. N Engl J Med. 1978 Aug 10;299(6):274–278. doi: 10.1056/NEJM197808102990603. [DOI] [PubMed] [Google Scholar]
  8. Elder G. H. Porphyria cutanea tarda. Semin Liver Dis. 1998;18(1):67–75. doi: 10.1055/s-2007-1007142. [DOI] [PubMed] [Google Scholar]
  9. Fargion S., Fracanzani A. L., Romano R., Cappellini M. D., Faré M., Mattioli M., Piperno A., Ronchi G., Fiorelli G. Genetic hemochromatosis in Italian patients with porphyria cutanea tarda: possible explanation for iron overload. J Hepatol. 1996 May;24(5):564–569. doi: 10.1016/s0168-8278(96)80141-3. [DOI] [PubMed] [Google Scholar]
  10. Fargion S., Piperno A., Cappellini M. D., Sampietro M., Fracanzani A. L., Romano R., Caldarelli R., Marcelli R., Vecchi L., Fiorelli G. Hepatitis C virus and porphyria cutanea tarda: evidence of a strong association. Hepatology. 1992 Dec;16(6):1322–1326. doi: 10.1002/hep.1840160603. [DOI] [PubMed] [Google Scholar]
  11. Feder J. N., Gnirke A., Thomas W., Tsuchihashi Z., Ruddy D. A., Basava A., Dormishian F., Domingo R., Jr, Ellis M. C., Fullan A. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996 Aug;13(4):399–408. doi: 10.1038/ng0896-399. [DOI] [PubMed] [Google Scholar]
  12. Felsher B. F., Kushner J. P. Hepatic siderosis and porphyria cutanea tarda: relation of iron excess to the metabolic defect. Semin Hematol. 1977 Apr;14(2):243–251. [PubMed] [Google Scholar]
  13. Garey J. R., Franklin K. F., Brown D. A., Harrison L. M., Metcalf K. M., Kushner J. P. Analysis of uroporphyrinogen decarboxylase complementary DNAs in sporadic porphyria cutanea tarda. Gastroenterology. 1993 Jul;105(1):165–169. doi: 10.1016/0016-5085(93)90022-5. [DOI] [PubMed] [Google Scholar]
  14. Garey J. R., Hansen J. L., Harrison L. M., Kennedy J. B., Kushner J. P. A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda. Blood. 1989 Mar;73(4):892–895. [PubMed] [Google Scholar]
  15. Garey J. R., Harrison L. M., Franklin K. F., Metcalf K. M., Radisky E. S., Kushner J. P. Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda. J Clin Invest. 1990 Nov;86(5):1416–1422. doi: 10.1172/JCI114856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gelb B. D., Edelson J. G., Desnick R. J. Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. Nat Genet. 1995 Jun;10(2):235–237. doi: 10.1038/ng0695-235. [DOI] [PubMed] [Google Scholar]
  17. Grandchamp B., De Verneuil H., Beaumont C., Chretien S., Walter O., Nordmann Y. Tissue-specific expression of porphobilinogen deaminase. Two isoenzymes from a single gene. Eur J Biochem. 1987 Jan 2;162(1):105–110. doi: 10.1111/j.1432-1033.1987.tb10548.x. [DOI] [PubMed] [Google Scholar]
  18. Grossman M. E., Bickers D. R., Poh-Fitzpatrick M. B., Deleo V. A., Harber L. C. Porphyria cutanea tarda. Clinical features and laboratory findings in 40 patients. Am J Med. 1979 Aug;67(2):277–286. doi: 10.1016/0002-9343(79)90403-0. [DOI] [PubMed] [Google Scholar]
  19. Jackson A. H., Sancovich H. A., Ferramola A. M., Evans N., Games D. E., Matlin S. A., Elder G. H., Smith S. G. Macrocyclic intermediates in the biosynthesis of porphyrins. Philos Trans R Soc Lond B Biol Sci. 1976 Feb 5;273(924):191–206. doi: 10.1098/rstb.1976.0009. [DOI] [PubMed] [Google Scholar]
  20. Kaya A. H., Plewinska M., Wong D. M., Desnick R. J., Wetmur J. G. Human delta-aminolevulinate dehydratase (ALAD) gene: structure and alternative splicing of the erythroid and housekeeping mRNAs. Genomics. 1994 Jan 15;19(2):242–248. doi: 10.1006/geno.1994.1054. [DOI] [PubMed] [Google Scholar]
  21. Kornreich R., Bishop D. F., Desnick R. J. Alpha-galactosidase A gene rearrangements causing Fabry disease. Identification of short direct repeats at breakpoints in an Alu-rich gene. J Biol Chem. 1990 Jun 5;265(16):9319–9326. [PubMed] [Google Scholar]
  22. Krawczak M., Reiss J., Cooper D. N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet. 1992 Sep-Oct;90(1-2):41–54. doi: 10.1007/BF00210743. [DOI] [PubMed] [Google Scholar]
  23. Kushner J. P., Barbuto A. J., Lee G. R. An inherited enzymatic defect in porphyria cutanea tarda: decreased uroporphyrinogen decarboxylase activity. J Clin Invest. 1976 Nov;58(5):1089–1097. doi: 10.1172/JCI108560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kószó F., Elder G. H., Roberts A., Simon N. Uroporphyrinogen decarboxylase deficiency in hepatoerythropoietic porphyria: further evidence for genetic heterogeneity. Br J Dermatol. 1990 Mar;122(3):365–370. doi: 10.1111/j.1365-2133.1990.tb08285.x. [DOI] [PubMed] [Google Scholar]
  25. Lai K., Langley S. D., Dembure P. P., Hjelm L. N., Elsas L. J., 2nd Duarte allele impairs biostability of galactose-1-phosphate uridyltransferase in human lymphoblasts. Hum Mutat. 1998;11(1):28–38. doi: 10.1002/(SICI)1098-1004(1998)11:1<28::AID-HUMU5>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  26. Lim C. K., Rideout J. M., Wright D. J. Separation of porphyrin isomers by high-performance liquid chromatography. Biochem J. 1983 May 1;211(2):435–438. doi: 10.1042/bj2110435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lundvall O., Weinfeld A., Lundin P. Iron storage in porphyria cutanea tarda. Acta Med Scand. 1970 Jul-Aug;1-2(1):37–53. doi: 10.1111/j.0954-6820.1970.tb08003.x. [DOI] [PubMed] [Google Scholar]
  28. McManus J. F., Begley C. G., Ratnaike S. Complex pattern of alternative splicing in the normal uroporphyrinogen decarboxylase gene: implications for diagnosis of familial porphyria cutanea tarda. Clin Chem. 1994 Oct;40(10):1884–1889. [PubMed] [Google Scholar]
  29. McManus J. F., Begley C. G., Sassa S., Ratnaike S. Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria. Blood. 1996 Nov 1;88(9):3589–3600. [PubMed] [Google Scholar]
  30. Meguro K., Fujita H., Ishida N., Akagi R., Kurihara T., Galbraith R. A., Kappas A., Zabriskie J. B., Toback A. C., Harber L. C. Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria. J Invest Dermatol. 1994 May;102(5):681–685. doi: 10.1111/1523-1747.ep12374134. [DOI] [PubMed] [Google Scholar]
  31. Moran-Jimenez M. J., Ged C., Romana M., Enriquez De Salamanca R., Taïeb A., Topi G., D'Alessandro L., de Verneuil H. Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am J Hum Genet. 1996 Apr;58(4):712–721. [PMC free article] [PubMed] [Google Scholar]
  32. Roberts A. G., Elder G. H., De Salamanca R. E., Herrero C., Lecha M., Mascaro J. M. A mutation (G281E) of the human uroporphyrinogen decarboxylase gene causes both hepatoerythropoietic porphyria and overt familial porphyria cutanea tarda: biochemical and genetic studies on Spanish patients. J Invest Dermatol. 1995 Apr;104(4):500–502. doi: 10.1111/1523-1747.ep12605953. [DOI] [PubMed] [Google Scholar]
  33. Roberts A. G., Whatley S. D., Morgan R. R., Worwood M., Elder G. H. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet. 1997 Feb 1;349(9048):321–323. doi: 10.1016/S0140-6736(96)09436-6. [DOI] [PubMed] [Google Scholar]
  34. Romana M., Dubart A., Beaupain D., Chabret C., Goossens M., Romeo P. H. Structure of the gene for human uroporphyrinogen decarboxylase. Nucleic Acids Res. 1987 Sep 25;15(18):7343–7356. doi: 10.1093/nar/15.18.7343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Romana M., Grandchamp B., Dubart A., Amselem S., Chabret C., Nordmann Y., Goossens M., Romeo P. H. Identification of a new mutation responsible for hepatoerythropoietic porphyria. Eur J Clin Invest. 1991 Apr;21(2):225–229. doi: 10.1111/j.1365-2362.1991.tb01814.x. [DOI] [PubMed] [Google Scholar]
  36. Roméo P. H., Raich N., Dubart A., Beaupain D., Pryor M., Kushner J., Cohen-Solal M., Goossens M. Molecular cloning and nucleotide sequence of a complete human uroporphyrinogen decarboxylase cDNA. J Biol Chem. 1986 Jul 25;261(21):9825–9831. [PubMed] [Google Scholar]
  37. Sampietro M., Piperno A., Lupica L., Arosio C., Vergani A., Corbetta N., Malosio I., Mattioli M., Fracanzani A. L., Cappellini M. D. High prevalence of the His63Asp HFE mutation in Italian patients with porphyria cutanea tarda. Hepatology. 1998 Jan;27(1):181–184. doi: 10.1002/hep.510270128. [DOI] [PubMed] [Google Scholar]
  38. Santos M., Clevers H. C., Marx J. J. Mutations of the hereditary hemochromatosis candidate gene HLA-H in porphyria cutanea tarda. N Engl J Med. 1997 May 1;336(18):1327–1328. doi: 10.1056/NEJM199705013361817. [DOI] [PubMed] [Google Scholar]
  39. Tsai S. F., Bishop D. F., Desnick R. J. Human uroporphyrinogen III synthase: molecular cloning, nucleotide sequence, and expression of a full-length cDNA. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7049–7053. doi: 10.1073/pnas.85.19.7049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Warner C. A., Yoo H. W., Roberts A. G., Desnick R. J. Congenital erythropoietic porphyria: identification and expression of exonic mutations in the uroporphyrinogen III synthase gene. J Clin Invest. 1992 Feb;89(2):693–700. doi: 10.1172/JCI115637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Whitby F. G., Phillips J. D., Kushner J. P., Hill C. P. Crystal structure of human uroporphyrinogen decarboxylase. EMBO J. 1998 May 1;17(9):2463–2471. doi: 10.1093/emboj/17.9.2463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Xu W., Warner C. A., Desnick R. J. Congenital erythropoietic porphyria: identification and expression of 10 mutations in the uroporphyrinogen III synthase gene. J Clin Invest. 1995 Feb;95(2):905–912. doi: 10.1172/JCI117742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yoo H. W., Warner C. A., Chen C. H., Desnick R. J. Hydroxymethylbilane synthase: complete genomic sequence and amplifiable polymorphisms in the human gene. Genomics. 1993 Jan;15(1):21–29. doi: 10.1006/geno.1993.1005. [DOI] [PubMed] [Google Scholar]
  44. de Verneuil H., Aitken G., Nordmann Y. Familial and sporadic porphyria cutanea: two different diseases. Hum Genet. 1978 Oct 31;44(2):145–151. doi: 10.1007/BF00295407. [DOI] [PubMed] [Google Scholar]
  45. de Verneuil H., Bourgeois F., de Rooij F., Siersema P. D., Wilson J. H., Grandchamp B., Nordmann Y. Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria. Hum Genet. 1992 Jul;89(5):548–552. doi: 10.1007/BF00219182. [DOI] [PubMed] [Google Scholar]
  46. de Verneuil H., Grandchamp B., Beaumont C., Picat C., Nordmann Y. Uroporphyrinogen decarboxylase structural mutant (Gly281----Glu) in a case of porphyria. Science. 1986 Nov 7;234(4777):732–734. doi: 10.1126/science.3775362. [DOI] [PubMed] [Google Scholar]
  47. de Verneuil H., Grandchamp B., Foubert C., Weil D., N'Guyen V. C., Gross M. S., Sassa S., Nordmann Y. Assignment of the gene for uroporphyrinogen decarboxylase to human chromosome 1 by somatic cell hybridization and specific enzyme immunoassay. Hum Genet. 1984;66(2-3):202–205. doi: 10.1007/BF00286601. [DOI] [PubMed] [Google Scholar]
  48. de Verneuil H., Grandchamp B., Nordmann Y. Some kinetic properties of human red cell uroporphyrinogen decarboxylase. Biochim Biophys Acta. 1980 Jan 11;611(1):174–186. doi: 10.1016/0005-2744(80)90053-4. [DOI] [PubMed] [Google Scholar]
  49. de Verneuil H., Grandchamp B., Romeo P. H., Raich N., Beaumont C., Goossens M., Nicolas H., Nordmann Y. Molecular analysis of uroporphyrinogen decarboxylase deficiency in a family with two cases of hepatoerythropoietic porphyria. J Clin Invest. 1986 Feb;77(2):431–435. doi: 10.1172/JCI112321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. de Verneuil H., Hansen J., Picat C., Grandchamp B., Kushner J., Roberts A., Elder G., Nordmann Y. Prevalence of the 281 (Gly----Glu) mutation in hepatoerythropoietic porphyria and porphyria cutanea tarda. Hum Genet. 1988 Jan;78(1):101–102. doi: 10.1007/BF00291248. [DOI] [PubMed] [Google Scholar]
  51. de Verneuil H., Sassa S., Kappas A. Purification and properties of uroporphyrinogen decarboxylase from human erythrocytes. A single enzyme catalyzing the four sequential decarboxylations of uroporphyrinogens I and III. J Biol Chem. 1983 Feb 25;258(4):2454–2460. [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES