Skip to main content
SpringerLink
Log in

Genetic and biochemical characterization of 16 acute intermittent porphyria cases with a high prevalence of the R173W mutation

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Summary

Acute intermittent porphyria (AIP) is a metabolic disease with a variable prevalence among different countries. In some areas of southern Europe it remains to be fully evaluated. We undertook a genetic and biochemical study of 16 unrelated Spanish AIP patients and relatives. The genetic analyses showed they harboured the following mutations in the porphobilinogen deaminase gene: R173W, G111R, L278P, L238P, R116W, R26C, 340insT, 730delCT, 691del30bp, and IVS14+1g>a. The mutation R173W was found in 6 patients (37.5%), including the only patients of our series with >3 recurrent porphyria attacks. While in clinical remission, all AIP patients exhibited sustained increased excretion of porphyrins and precursors. PBG excretion showed a high between-subject variation and was not related to erythrocyte PBG deaminase activity. The study of family members allowed the identification of 22 asymptomatic AIP carriers. These included 8 persons harbouring the R173W mutation belonging to four different families. Six of these latent AIP subjects showed increased PBG elimination, and in two the urinary levels were >10-fold the normal limit. These results reinforce the hypothesis that the R173W mutation may have a high biochemical and clinical penetrance among AIP patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AIP:

intermittent porphyria

ALA:

aminolevulinic acid

IDIBAPS:

Institut d’Investigació Biomèdica Agustí Pi i Sunyer

PBG:

porphobilinogen

PBGD:

porphobilinogen deaminase

SSCP:

single-strand conformation polymorphism analysis

References

  • Aarsand AK, Petersen PH, Sandberg S (2006) Estimation and application of biological variation of urinary delta-aminolevulinic acid and porphobilinogen in healthy individuals and in patients with acute intermittent porphyria. Clin Chem 52: 650–656.

    Article  PubMed  CAS  Google Scholar 

  • Anderson KE (1989) LHRH analogues for hormonal manipulation in acute intermittent porphyria. Semin Hematol 26: 10–15.

    PubMed  CAS  Google Scholar 

  • Anderson KE, Bloomer JR, Bonkovsky HL, et al (2005) Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 142: 439–450.

    PubMed  Google Scholar 

  • Andersson C, Floderus Y, Wikberg A, Lithner F (2000) The W198X and R173W mutations in the porphobilinogen deaminase gene in acute intermittent porphyria have higher clinical penetrance than R167W. A population-based study. Scand J Clin Lab Invest 60: 643–648.

    Article  PubMed  CAS  Google Scholar 

  • Badenas C, Torra R, Lucero L, Milá M, Estivill X, Darnell A (1999) Mutational analysis within the 3′ region of the PKD1 gene. Kidney Int 55: 1225–1233.

    Article  PubMed  CAS  Google Scholar 

  • Badminton MN, Elder GH (2005) Molecular mechanisms of dominant expression in porphyria. J Inherit Metab Dis 28: 277–286.

    Article  PubMed  CAS  Google Scholar 

  • Beukeveld GJJ; Wolthers BG; Nordmann Y, Deybach JC, Grandchamp B, Wadman SK (1990) A retrospective study of a patient with homozygous form of acute intermittent porphyria. J Inherit Metab Dis 13: 673–683.

    Article  PubMed  CAS  Google Scholar 

  • De Siervi A, Rossetti MV, Parera VE, et al (1999) Identification and characterization of hydroxymethylbilane synthase mutations causing acute intermittent porphyria: evidence for an ancestral founder of the common G111R mutation. Am J Med Genet 86: 366–375.

    Article  PubMed  Google Scholar 

  • den Dunnen JT, Antonarakis E (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15: 7–12.

    Article  Google Scholar 

  • Erlandsen EJ, Jorgensen PE, Markussen S, Brock A (2000) Determination of porphobilinogen deaminase activity in human erythrocytes: pertinent factors in obtaining optimal conditions for measurements. Scand J Clin Lab Invest 60: 627–634.

    Article  PubMed  CAS  Google Scholar 

  • Grandchamp B, de Verneuil H, Beaumont C, Chrétien S, Walter O, Nordmann Y (1987) Tissue-specific expression of porphobilinogen deaminase. Two isozymes from a single gene. Eur J Biochem 162: 105–110.

    Article  PubMed  CAS  Google Scholar 

  • Greene-Davis ST, Neumann PE, Mann OE, et al (1997) Detection of a R173W mutation in the porphobilinogen deaminase gene in the Nova Scotian “foreign Protestant” population with acute intermittent porphyria: a founder effect. Clin Biochem 30: 607–612.

    Article  PubMed  CAS  Google Scholar 

  • Gu XF, de Rooij F, Lee JS et al (1993) High prevalence of a point mutation in the porphobilinogen deaminase gene in Dutch patients with acute intermittent porphyria. Hum Genet 91: 128–130.

    Article  PubMed  CAS  Google Scholar 

  • Guillen-Navarro E, Carbonell P, Glover G, Sanchez-Solis M, Fernandez-Barreiro A (2004) Novel HMBS founder mutation and significant intronic polymorphism in Spanish patients with acute intermittent porphyria. Ann Hum Genet 68: 509–514.

    Article  PubMed  CAS  Google Scholar 

  • Handschin C, Lin J, Rhee J, et al (2005) Nutritional regulation of hepatic haem biosynthesis and porphyria through PGC-1alpha. Cell 122: 505–515.

    Article  PubMed  CAS  Google Scholar 

  • Hindmarsh JT, Oliveras L, Greenway DC (1999) Biochemical differentiation of the porphyrias. Clin Biochem 32: 609–619.

    Article  PubMed  CAS  Google Scholar 

  • Jacob K, Egeler E, Gross U, Doss MO (1999) Investigations on the formation of urinary coproporphyrin isomers I–IV in 5-aminolevulinic acid dehydratase deficiency porphyria, acute lead intoxication and after oral 5-aminolevulinic acid loading. Clin Biochem 32: 119–123.

    Article  PubMed  CAS  Google Scholar 

  • Kauppinen R (2005) Porphyrias. Lancet 365: 241–252.

    PubMed  CAS  Google Scholar 

  • Kauppinen R, von und zu Fraunberg M (2002) Molecular and biochemical studies of acute intermittent porphyria in 196 patients and their families. Clin Chem 48: 1891–1900.

    PubMed  CAS  Google Scholar 

  • Kauppinen R, Mustajoki P (1992) Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore) 71: 1–13.

    CAS  Google Scholar 

  • Kauppinen R, Mustajoki S, Pihlaja H, Peltonen L, Mustajoki P (1995) Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene. Hum Mol Genet 4: 215–222.

    PubMed  CAS  Google Scholar 

  • Lim CK, Peters TJ (1984) Urine and faecal porphyrin profiles by reversed-phase high-performance liquid chromatography in the porphyrias. Clin Chim Acta 139: 55–63.

    Article  PubMed  CAS  Google Scholar 

  • Meyer UA, Strand LJ, Doss M, Rees AC, Marver HS (1972) Intermittent acute porphyria—demonstration of a genetic defect in porphobilinogen metabolism. N Engl J Med 286: 1277–1282.

    Article  PubMed  CAS  Google Scholar 

  • Miller SA, Dykes DD, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16: 12–15.

    Google Scholar 

  • Mustajoki P, Kauppinen R, Lannfelt L, Lilius L, Koistinen J (1992) Frequency of low erythrocyte porphobilinogen deaminase activity in Finland. J Intern Med 231: 389–395.

    Article  PubMed  CAS  Google Scholar 

  • Mustajoki S, Pihlaja H, Ahola H, Petersen NE, Mustajoki P, Kauppinen R (1998) Three splicing defects, an insertion, and two missense mutations responsible for acute intermittent porphyria. Hum Genet 102: 541–548.

    Article  PubMed  CAS  Google Scholar 

  • Mustajoki S, Laine M, Lahtela M, Mustajoki P, Peltonen L, Kauppinen R (2000) Acute intermittent porphyria: expression of mutant and wild-type porphobilinogen deaminase in COS-1 cells. Mol Med 6: 670–679.

    PubMed  CAS  Google Scholar 

  • Namba H, Narahara K, Tsuji K, Yokoyama Y, Seino Y (1991) Assignment of human PBG deaminase to 11q24.1-q24.2 by in situ hybridization and gene dosage studies. Cytogenet Cell Genet 57: 105–108.

    Article  PubMed  CAS  Google Scholar 

  • Nordmann Y, Puy H, Deybach JC (1999) The porphyrias. J Hepatol 30: 12–16.

    PubMed  Google Scholar 

  • Puy H, Deybach JC, Lamoril J, et al (1997) Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. Am J Hum Genet 60: 1373–1383.

    PubMed  CAS  Google Scholar 

  • Solis C, Lopez-Echaniz I, Sefarty-Graneda D, Astrin KH, Desnick RJ (1999) Identification and expression of mutations in the hydroxymethylbilane synthase gene causing acute intermittent porphyria (AIP). Mol Med 5: 664–671.

    PubMed  CAS  Google Scholar 

  • Solis C, Martinez-Bermejo A, Naidich TP, et al (2004) Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch Neurol 61: 1764–1770.

    Article  PubMed  Google Scholar 

  • Thunell S (2000) Porphyrins, porphyrin metabolism and porphyrias I. Update. Scand J Clin Lab Invest 60: 509–540.

    Article  PubMed  CAS  Google Scholar 

  • Thunell S, Harper P, Brock A, Petersen NE (2000) Porphyrins, porphyrin metabolism and porphyrias. II. Diagnosis and monitoring in the acute porphyrias. Scand J Clin Lab Invest 60: 541–559.

    Article  PubMed  CAS  Google Scholar 

  • Von und zu Fraunberg M, Pischik E, Udd L, Kauppinen R (2005) Clinical and biochemical characteristics and genotype–phenotype correlation in 143 Finnish and Russian patients with acute intermittent porphyria. Medicine (Baltimore) 84: 35–47.

    Article  Google Scholar 

  • Whatley SD, Roberts AG, Llewellyn DH, Bennett CP, Garrett C, Elder GH (2000). Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene. Hum Genet 107: 243–248.

    Article  PubMed  CAS  Google Scholar 

  • Yoo H, Warner C, Chen C, Desnick R (1993) Hydroxymethylbilane synthase: complete genomic sequence and amplifiable polymorphisms in the human gene. Genomics 15: 21–29.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biochemistry and Molecular Genetics Unit, Dermatology Unit, Hospital Clínic i Provincial, IDIBAPS, University of Barcelona, Barcelona, Spain

    J. To-Figueras, C. Badenas, C. Carrera, C. Muñoz, M. Milá, M. Lecha & C. Herrero

Authors
  1. J. To-Figueras
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Badenas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Carrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Milá
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Lecha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. Herrero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. To-Figueras.

Additional information

Communicating editor: Verena Peters

Competing interests: None declared

Rights and permissions

Reprints and permissions

About this article

Cite this article

To-Figueras, J., Badenas, C., Carrera, C. et al. Genetic and biochemical characterization of 16 acute intermittent porphyria cases with a high prevalence of the R173W mutation. J Inherit Metab Dis 29, 580–585 (2006). https://doi.org/10.1007/s10545-006-0344-6

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-006-0344-6

Keywords

Search

Navigation