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Human Genetics

, Volume 97, Issue 1, pp 51–59 | Cite as

Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship

  • J. K. Ploos van Amstel
  • A. J. I. W. Bergman
  • E. A. C. M. van Beurden
  • J. F. M. Roijers
  • T. Peelen
  • I. E. T. van den Berg
  • B. T. Poll-The
  • E. A. Kvittingen
  • R. Berger
Original Investigation

Abstract

The complete fumarylacetoacetate hydrolase (FAH) genotype of probands of thirteen unrelated families with hereditary tyrosinemia type 1 (HT 1) was established. The screening was performed by analysis of exons 2–14 of the FAH gene by using the polymerase chain reaction (PCR) and of the mRNA by reverse transcription/PCR. Nine different mutations were identified, of which six are novel. Three mutations involve consensus sequences for correct splicing, viz. IVS 6-1 (g-t), IVS 7-1 (g-a) and IVS 12+5 (g-a). Two missense mutations (C193R and G369V) and three nonsense mutations (R237X, E357X and E364X) were found. One silent mutation N232N was associated with the skipping of exon 8 from the FAH mRNA. Analysis of the effect of the respective mutations on the FAH mRNA showed a strong reduction of FAH mRNA levels in association with the nonsense mutations, and normal levels with the missense mutations. The splice consensus mutations give deletions of complete or small parts of exon sequences from the FAH mRNA. Data suggest a founder effect for several of the mutations, with a frequency for both the IVS 6-1 (g-t) and IVS 12+5 (g-a) mutations of approximately 30% in the HT 1 probands. No strict correlation between genotype and phenotype, i.e. the acute, subacute or chronic form of HT 1, was evident.

Keywords

Consensus Sequence Missense Mutation Nonsense Mutation Strong Reduction Founder Effect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • J. K. Ploos van Amstel
    • 1
  • A. J. I. W. Bergman
    • 2
  • E. A. C. M. van Beurden
    • 2
  • J. F. M. Roijers
    • 1
    • 2
  • T. Peelen
    • 1
  • I. E. T. van den Berg
    • 2
  • B. T. Poll-The
    • 2
  • E. A. Kvittingen
    • 3
  • R. Berger
    • 2
  1. 1.DNA laboratory, Clinical Genetics Center UtrechtCA UtrechtThe Netherlands
  2. 2.Laboratory for Metabolic DiseaseWilhelmina Children's HospitalUtrechtThe Netherlands
  3. 3.Institute of Clinical BiochemistryUniversity of OsloOsloNorway

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