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Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase.

Phillips JD, Parker TL, Schubert HL, Whitby FG, Hill CP, Kushner JP
Blood 98 3179-85 (2001)
Related entries: 1jph, 1jpk

Cited: 18 times
EuropePMC logo PMID: 11719352

Abstract

Functional consequences of 12 mutations-10 missense, 1 splicing defect, and 1 frameshift mutation-were characterized in the uroporphyrinogen decarboxylase (URO-D) gene found in Utah pedigrees with familial porphyria cutanea tarda (F-PCT). All but one mutation altered a restriction site in the URO-D gene, permitting identification of affected relatives using a combination of polymerase chain reaction and restriction enzyme digestion. In a bacterial expression system, 3 of the missense mutants were found in inclusion bodies, but 7 were expressed as soluble proteins. Enzymatic activity of soluble, recombinant mutant URO-D genes ranged from 29% to 94% of normal. URO-D mRNA levels in Epstein-Barr-virus transformed cells derived from patients were normal (with the exception of the frameshift mutation) even though protein levels were lower than normal, suggesting that missense mutations generally cause unstable URO-Ds in vivo. The crystal structures of 3 mutant URO-Ds were solved, and the structural consequences of the mutations were defined. All missense mutations reported here and by others were mapped to the crystal structure of URO-D, and structural effects were predicted. These studies define structural and functional consequences of URO-D mutations occurring in patients with F-PCT.

Reviews citing this publication (2)

  1. Molecular basis of inherited diseases: a structural perspective. Steward RE, MacArthur MW, Laskowski RA, Thornton JM. Trends Genet 19 505-513 (2003)
  2. Heme biosynthesis and the porphyrias. Phillips JD. Mol Genet Metab 128 164-177 (2019)

Articles citing this publication (16)

  1. Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance. Malay AD, Allen KN, Tolan DR. J Mol Biol 347 135-144 (2005)
  2. Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives. Badenas C, To-Figueras J, Phillips JD, Warby CA, Muñoz C, Herrero C. Clin Genet 75 346-353 (2009)
  3. Letter Abnormal concentration of porphyrins in serum from COVID-19 patients. San Juan I, Bruzzone C, Bizkarguenaga M, Bernardo-Seisdedos G, Laín A, Gil-Redondo R, Diercks T, Gil-Martínez J, Urquiza P, Arana E, Seco M, García de Vicuña A, Embade N, Mato JM, Millet O. Br J Haematol 190 e265-e267 (2020)
  4. Down-regulation of hepcidin in porphyria cutanea tarda. Ajioka RS, Phillips JD, Weiss RB, Dunn DM, Smit MW, Proll SC, Katze MG, Kushner JP. Blood 112 4723-4728 (2008)
  5. Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Armstrong DK, Sharpe PC, Chambers CR, Whatley SD, Roberts AG, Elder GH. Br J Dermatol 151 920-923 (2004)
  6. Substrate shuttling between active sites of uroporphyrinogen decarboxylase is not required to generate coproporphyrinogen. Phillips JD, Warby CA, Whitby FG, Kushner JP, Hill CP. J Mol Biol 389 306-314 (2009)
  7. The molecular basis of porphyria cutanea tarda in Chile: identification and functional characterization of mutations in the uroporphyrinogen decarboxylase gene. Poblete-Gutiérrez P, Mendez M, Wiederholt T, Merk HF, Fontanellas A, Wolff C, Frank J. Exp Dermatol 13 372-379 (2004)
  8. Molecular heterogeneity of familial porphyria cutanea tarda in Spain: characterization of 10 novel mutations in the UROD gene. Méndez M, Poblete-Gutiérrez P, García-Bravo M, Wiederholt T, Morán-Jiménez MJ, Merk HF, Garrido-Astray MC, Frank J, Fontanellas A, Enríquez de Salamanca R. Br J Dermatol 157 501-507 (2007)
  9. Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP). Phillips JD, Whitby FG, Stadtmueller BM, Edwards CQ, Hill CP, Kushner JP. Transl Res 149 85-91 (2007)
  10. Identification of a mutation in the ovine uroporphyrinogen decarboxylase (UROD) gene associated with a type of porphyria. Nezamzadeh R, Seubert A, Pohlenz J, Brenig B. Anim Genet 36 297-302 (2005)
  11. The first branching point in porphyrin biosynthesis: a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase. Bushnell EA, Erdtman E, Llano J, Eriksson LA, Gauld JW. J Comput Chem 32 822-834 (2011)
  12. ALAD Inhibition by Porphobilinogen Rationalizes the Accumulation of δ-Aminolevulinate in Acute Porphyrias. San Juan I, Pereira-Ortuzar T, Cendoya X, Laín A, To-Figueras J, Mateos B, Planes FJ, Bernardo-Seisdedos G, Mato JM, Millet O. Biochemistry 61 2409-2416 (2022)
  13. Expression and characterization of six clinically relevant uroporphyrinogen decarboxylase gene mutations. Christiansen L, Brøns-Poulsen J, Hørder M, Brock A, Petersen NE. Scand J Clin Lab Invest 65 227-235 (2005)
  14. Familial porphyria cutanea tarda in Spain: characterization of eight novel mutations in the UROD gene and haplotype analysis of the common p.G281E mutation. Gómez-Abecia S, Morán-Jiménez MJ, Ruiz-Casares E, Henriques-Gil N, García-Pastor I, Garrido-Astray MC, Enríquez de Salamanca R, Méndez M. Gene 522 89-95 (2013)
  15. Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. To-Figueras J, Phillips JD, Gonzalez-López JM, Badenas C, Madrigal I, González-Romarís EM, Ramos C, Aguirre JM, Herrero C. Br J Dermatol 165 499-505 (2011)
  16. Structural and kinetic characterization of mutant human uroporphyrinogen decarboxylases. Warby CA, Phillips JD, Bergonia HA, Whitby FG, Hill CP, Kushner JP. Cell Mol Biol (Noisy-le-grand) 55 40-45 (2009)


Related citations provided by authors (1)

  1. Crystal Structure of human uroporphyrinogen decarboxylase. Whitby FG, Phillips JD, Kushner JP, Hill CP EMBO J. 17 2463-2471 (1998)

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