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

Marten H. Hofker, Toshihiro Nukiwa, Heleen M.B. van Paassen, Marcel Nelen, Johannes A. Kramps, Eduard C. Klasen, Rune R. Frants, Ronald Crystal

Research output: Contribution to journalArticle

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Abstract

The molecular defect has been elucidated in the alpha-1-antitrypsin (PI) gene of a patient with a serum level of only 5 mg/100 ml and a PI M-like phenotype, designated PI MHeerlen. The restriction fragment patterns obtained by probes covering the whole gene and flanking sequences were normal, suggesting no major rearrangements. The nucleotide sequence of the exons, intron/exon junctions, and a part of the promoter region is similar to that of a PI M1(Ala213) gene except for an C→T mutation in codon 369, causing a Pro→Leu substitution. Haplotype analysis and oligonucleotide hybridization studies demonstrated the homozygous state of the mutation in the index case. It is most likely that the Pro369→Leu substitution is responsible for the low serum alpha-1-antitrypsin concentration of the patient because this mutation is solely confined to the PI MHeerlen allele and no other relevant mutations could be revealed. As proline is important for the secondary and tertiary structure of proteins, the mutation may cause an abnormal processing of the nascent polypeptide. The same mutation was observed in two unrelated subjects known to carry a PI allele giving a low serum alpha-1-antitrypsin level.

Original languageEnglish
Pages (from-to)264-268
Number of pages5
JournalHuman Genetics
Volume81
Issue number3
DOIs
Publication statusPublished - 1 Feb 1989
Externally publishedYes

Fingerprint

alpha 1-Antitrypsin Deficiency
Codon
alpha 1-Antitrypsin
Mutation
Exons
Serum
Alleles
Genes
Secondary Protein Structure
Tertiary Protein Structure
Genetic Promoter Regions
Proline
Oligonucleotides
Introns
Haplotypes
Autosomal Recessive alpha-1-Antitrypsin Deficiency
Phenotype
Peptides

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Hofker, M. H., Nukiwa, T., van Paassen, H. M. B., Nelen, M., Kramps, J. A., Klasen, E. C., ... Crystal, R. (1989). A Pro → Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen. Human Genetics, 81(3), 264-268. https://doi.org/10.1007/BF00279001

A Pro → Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen. / Hofker, Marten H.; Nukiwa, Toshihiro; van Paassen, Heleen M.B.; Nelen, Marcel; Kramps, Johannes A.; Klasen, Eduard C.; Frants, Rune R.; Crystal, Ronald.

In: Human Genetics, Vol. 81, No. 3, 01.02.1989, p. 264-268.

Research output: Contribution to journalArticle

Hofker, MH, Nukiwa, T, van Paassen, HMB, Nelen, M, Kramps, JA, Klasen, EC, Frants, RR & Crystal, R 1989, 'A Pro → Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen', Human Genetics, vol. 81, no. 3, pp. 264-268. https://doi.org/10.1007/BF00279001
Hofker MH, Nukiwa T, van Paassen HMB, Nelen M, Kramps JA, Klasen EC et al. A Pro → Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen. Human Genetics. 1989 Feb 1;81(3):264-268. https://doi.org/10.1007/BF00279001
Hofker, Marten H. ; Nukiwa, Toshihiro ; van Paassen, Heleen M.B. ; Nelen, Marcel ; Kramps, Johannes A. ; Klasen, Eduard C. ; Frants, Rune R. ; Crystal, Ronald. / A Pro → Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen. In: Human Genetics. 1989 ; Vol. 81, No. 3. pp. 264-268.
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