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Related Experiment Videos

Recurrent deletion in the human antithrombin III gene.

C B Grundy1, F Thomas, D S Millar

  • 1Charter Molecular Genetics Laboratory, Thrombosis Research Institute, Chelsea, London, UK.

Blood
|August 15, 1991
PubMed
Summary

Two patients with hereditary antithrombin III (ATIII) deficiency and thrombosis had frameshift mutations in the ATIII gene. These mutations occurred at a specific GAG codon, suggesting sequence-directed deletions in human genes.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Hematology

Background:

  • Hereditary antithrombin III (ATIII) deficiency is a rare genetic disorder associated with an increased risk of venous thromboembolism.
  • Type I ATIII deficiency is characterized by reduced levels of both ATIII activity and antigen.

Purpose of the Study:

  • To investigate the genetic basis of hereditary ATIII deficiency in patients with recurrent thromboembolism.
  • To identify specific mutations within the ATIII gene responsible for Type I deficiency.
  • To explore potential patterns of non-random mutations in human genes.

Main Methods:

  • Polymerase chain reaction (PCR) and direct sequencing of ATIII gene exon-coding regions were performed.
  • Genetic analysis was conducted on eight unrelated patients diagnosed with heterozygous Type I ATIII deficiency.

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  • A comprehensive literature search was performed to identify other deletion 'hotspots' in human genes.

    • Main Results:

    • Two unrelated patients presented with frameshift mutations (one-base and two-base deletions) within exon 4 of the ATIII gene at the same GAG codon (Glu 245).
    • Six additional deletion-prone sites were identified in four other human genes.
    • A consensus sequence (T G A/G A/G G A/C) was derived from these deletion-prone sites, indicating sequence homology.

    Conclusions:

    • The findings suggest that specific codons, like GAG at position 245 in the ATIII gene, may be mutation hotspots for deletions.
    • The identified consensus sequence implies that deletions in human genes might be non-random and directed by specific DNA sequences.
    • This research contributes to understanding the molecular mechanisms underlying hereditary thrombophilia and provides insights into gene mutation patterns.