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A Pro----Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen

M H Hofker1, T Nukiwa, H M van Paassen

  • 1Department of Human Genetics, Sylvius Laboratories, State University of Leiden, The Netherlands.

Human Genetics
|February 1, 1989
PubMed

Insights

A novel mutation in the alpha-1-antitrypsin (PI) gene, Pro369Leu, was identified in a patient with severely low serum PI levels. This genetic defect likely impairs protein processing, leading to reduced circulating PI concentrations.

Area of Science:

  • Genetics
  • Molecular Biology
  • Biochemistry

Background:

  • Alpha-1-antitrypsin (PI) deficiency is a genetic disorder associated with low serum PI levels.
  • Identifying the molecular basis of PI deficiency is crucial for understanding disease mechanisms.

Purpose of the Study:

  • To elucidate the molecular defect in the alpha-1-antitrypsin (PI) gene of a patient with extremely low serum PI levels and a PI M-like phenotype.

Main Methods:

  • Restriction fragment analysis to detect major gene rearrangements.
  • Nucleotide sequencing of exons, intron/exon junctions, and promoter regions.
  • Haplotype analysis and oligonucleotide hybridization to confirm homozygous mutation.

Main Results:

  • No major rearrangements were found in the PI gene.
  • A C-to-T mutation in codon 369, resulting in a Pro369Leu substitution, was identified.
  • This mutation was homozygous in the patient and present in two other unrelated individuals with low PI levels.

Conclusions:

  • The Pro369Leu substitution in the PI gene is the likely cause of the patient's low serum PI concentration.
  • This mutation may lead to abnormal processing of the alpha-1-antitrypsin protein.
  • The identified mutation represents a novel genetic cause of PI deficiency.

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