Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1996 May;33(5):437–438. doi: 10.1136/jmg.33.5.437

Acute intermittent porphyria caused by defective splicing of porphobilinogen deaminase RNA: a synonymous codon mutation at -22 bp from the 5' splice site causes skipping of exon 3.

D H Llewellyn 1, G A Scobie 1, A J Urquhart 1, S D Whatley 1, A G Roberts 1, P R Harrison 1, G H Elder 1
PMCID: PMC1050621  PMID: 8733062

Abstract

Acute intermittent porphyria (AIP) results from mutations in the porphobilinogen deaminase (PBG) gene. Three of 14 randomly selected, unrelated patients with the cross reacting immunological material (CRIM) negative form of AIP were found to have previously undescribed RNA splicing defects. Defective splicing of exons 12 and 13 was caused by a C-->G transversion at position -3 of the 3' splice site of intron 11 and a G-->A transition at the first position of intron 13, respectively. Defective splicing of exon 3 was associated with a synonymous codon mutation (CGC-->CGG, R28R) at position -22 from the 5' splice site. Our findings are consistent with previous reports indicating that about 15% of mutations in the PBG deaminase gene that cause AIP affect RNA splicing and add to the evidence that synonymous intraexonic codon mutations may cause disease.

Full text

PDF
437

Images in this article

437Image
on p.437
438Image
on p.438

Selected References

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

  1. 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]
  2. Fukao T., Yamaguchi S., Wakazono A., Orii T., Hoganson G., Hashimoto T. Identification of a novel exonic mutation at -13 from 5' splice site causing exon skipping in a girl with mitochondrial acetoacetyl-coenzyme A thiolase deficiency. J Clin Invest. 1994 Mar;93(3):1035–1041. doi: 10.1172/JCI117052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Grandchamp B., Picat C., de Rooij F., Beaumont C., Wilson P., Deybach J. C., Nordmann Y. A point mutation G----A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria. Nucleic Acids Res. 1989 Aug 25;17(16):6637–6649. doi: 10.1093/nar/17.16.6637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Kauppinen R., Mustajoki S., Pihlaja H., Peltonen L., Mustajoki P. Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene. Hum Mol Genet. 1995 Feb;4(2):215–222. doi: 10.1093/hmg/4.2.215. [DOI] [PubMed] [Google Scholar]
  5. Llewellyn D. H., Elder G. H., Kalsheker N. A., Marsh O. W., Harrison P. R., Grandchamp B., Picat C., Nordmann Y., Romeo P. H., Goossens M. DNA polymorphism of human porphobilinogen deaminase gene in acute intermittent porphyria. Lancet. 1987 Sep 26;2(8561):706–708. doi: 10.1016/s0140-6736(87)91073-7. [DOI] [PubMed] [Google Scholar]
  6. Richard I., Beckmann J. S. How neutral are synonymous codon mutations? Nat Genet. 1995 Jul;10(3):259–259. doi: 10.1038/ng0795-259. [DOI] [PubMed] [Google Scholar]
  7. Ricketts M. H., Simons M. J., Parma J., Mercken L., Dong Q., Vassart G. A nonsense mutation causes hereditary goitre in the Afrikander cattle and unmasks alternative splicing of thyroglobulin transcripts. Proc Natl Acad Sci U S A. 1987 May;84(10):3181–3184. doi: 10.1073/pnas.84.10.3181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Steingrimsdottir H., Rowley G., Dorado G., Cole J., Lehmann A. R. Mutations which alter splicing in the human hypoxanthine-guanine phosphoribosyltransferase gene. Nucleic Acids Res. 1992 Mar 25;20(6):1201–1208. doi: 10.1093/nar/20.6.1201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Wong C., Antonarakis S. E., Goff S. C., Orkin S. H., Forget B. G., Nathan D. G., Giardina P. J., Kazazian H. H., Jr Beta-thalassemia due to two novel nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene. Blood. 1989 Mar;73(4):914–918. [PubMed] [Google Scholar]
  10. Zuker M., Stiegler P. Optimal computer folding of large RNA sequences using thermodynamics and auxiliary information. Nucleic Acids Res. 1981 Jan 10;9(1):133–148. doi: 10.1093/nar/9.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES