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Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations.
Mol Genet Metab. 2019 11; 128(3):363-366.MG

Abstract

Porphyria Cutanea Tarda (PCT) is a cutaneous porphyria that results from the hepatic inhibition of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD), and can occur either in the absence or presence of an inherited heterozygous UROD mutation (PCT subtypes 1 and 2, respectively). A heterozygous UROD mutation causes half-normal levels of UROD activity systemically, which is a susceptibility factor but is not sufficient alone to cause type 2 PCT. In both Types 1 and 2 PCT, the cutaneous manifestations are precipitated by additional factors that lead to generation of an inhibitor that more profoundly reduces hepatic UROD activity. PCT is an iron-related disorder, and many of its known susceptibility factors, which include infections (e.g. hepatitis C virus, HIV), high alcohol consumption, smoking, estrogens, and genetic traits (e.g. hemochromatosis mutations) can increase hepatic iron accumulation. Hepatoerythropoietic Porphyria (HEP) is a rare autosomal recessive disease that results from homozygosity or compound heterozygosity for UROD mutations and often causes infantile or childhood onset of both erythropoietic and cutaneous manifestations. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for 387 unrelated patients with PCT and four unrelated patients with HEP. Of the 387 unrelated individuals tested for Type 2 PCT, 79 (20%) were heterozygous for UROD mutations. Among 26 family members of mutation-positive PCT patients, eight (31%) had the respective family mutation. Additionally, of the four unrelated HEP patients referred for UROD mutation analyses, all had homozygosity or compound heterozygosity for UROD mutations, and all eight asymptomatic family members were heterozygotes for UROD mutations. Of the UROD mutations identified, 19 were novel, including nine missense, two nonsense, one consensus splice-site, and seven insertions and deletions. These results expand the molecular heterogeneity of PCT and HEP by adding a total of 19 novel UROD mutations. Moreover, the results document the usefulness of molecular testing to confirm a genetic susceptibility trait in Type 2 PCT, confirm a diagnosis in HEP, and identify heterozygous family members.

Authors+Show Affiliations

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: yedidyah.weiss@mssm.edu.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: brenden.chen@mssm.edu.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: makiko.yasuda@mssm.edu.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: irina.nazarenko@mssm.edu.Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: kanderso@utmb.edu.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: robert.desnick@mssm.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30514647

Citation

Weiss, Yedidyah, et al. "Porphyria Cutanea Tarda and Hepatoerythropoietic Porphyria: Identification of 19 Novel Uroporphyrinogen III Decarboxylase Mutations." Molecular Genetics and Metabolism, vol. 128, no. 3, 2019, pp. 363-366.
Weiss Y, Chen B, Yasuda M, et al. Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations. Mol Genet Metab. 2019;128(3):363-366.
Weiss, Y., Chen, B., Yasuda, M., Nazarenko, I., Anderson, K. E., & Desnick, R. J. (2019). Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations. Molecular Genetics and Metabolism, 128(3), 363-366. https://doi.org/10.1016/j.ymgme.2018.11.013
Weiss Y, et al. Porphyria Cutanea Tarda and Hepatoerythropoietic Porphyria: Identification of 19 Novel Uroporphyrinogen III Decarboxylase Mutations. Mol Genet Metab. 2019;128(3):363-366. PubMed PMID: 30514647.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations. AU - Weiss,Yedidyah, AU - Chen,Brenden, AU - Yasuda,Makiko, AU - Nazarenko,Irina, AU - Anderson,Karl E, AU - Desnick,Robert J, Y1 - 2018/11/28/ PY - 2018/10/18/received PY - 2018/11/27/revised PY - 2018/11/27/accepted PY - 2018/12/6/pubmed PY - 2018/12/6/medline PY - 2018/12/6/entrez KW - Cutaneous porphyrias KW - Hepatoerythropoietic porphyria KW - Mutation analysis KW - Porphyria cutanea tarda KW - Uroporphyrinogen decarboxylase SP - 363 EP - 366 JF - Molecular genetics and metabolism JO - Mol. Genet. Metab. VL - 128 IS - 3 N2 - Porphyria Cutanea Tarda (PCT) is a cutaneous porphyria that results from the hepatic inhibition of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD), and can occur either in the absence or presence of an inherited heterozygous UROD mutation (PCT subtypes 1 and 2, respectively). A heterozygous UROD mutation causes half-normal levels of UROD activity systemically, which is a susceptibility factor but is not sufficient alone to cause type 2 PCT. In both Types 1 and 2 PCT, the cutaneous manifestations are precipitated by additional factors that lead to generation of an inhibitor that more profoundly reduces hepatic UROD activity. PCT is an iron-related disorder, and many of its known susceptibility factors, which include infections (e.g. hepatitis C virus, HIV), high alcohol consumption, smoking, estrogens, and genetic traits (e.g. hemochromatosis mutations) can increase hepatic iron accumulation. Hepatoerythropoietic Porphyria (HEP) is a rare autosomal recessive disease that results from homozygosity or compound heterozygosity for UROD mutations and often causes infantile or childhood onset of both erythropoietic and cutaneous manifestations. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for 387 unrelated patients with PCT and four unrelated patients with HEP. Of the 387 unrelated individuals tested for Type 2 PCT, 79 (20%) were heterozygous for UROD mutations. Among 26 family members of mutation-positive PCT patients, eight (31%) had the respective family mutation. Additionally, of the four unrelated HEP patients referred for UROD mutation analyses, all had homozygosity or compound heterozygosity for UROD mutations, and all eight asymptomatic family members were heterozygotes for UROD mutations. Of the UROD mutations identified, 19 were novel, including nine missense, two nonsense, one consensus splice-site, and seven insertions and deletions. These results expand the molecular heterogeneity of PCT and HEP by adding a total of 19 novel UROD mutations. Moreover, the results document the usefulness of molecular testing to confirm a genetic susceptibility trait in Type 2 PCT, confirm a diagnosis in HEP, and identify heterozygous family members. SN - 1096-7206 UR - https://www.unboundmedicine.com/medline/citation/30514647/Porphyria_cutanea_tarda_and_hepatoerythropoietic_porphyria:_Identification_of_19_novel_uroporphyrinogen_III_decarboxylase_mutations_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1096-7192(18)30642-5 DB - PRIME DP - Unbound Medicine ER -