Rare deficiency {alpha}{sub 1} Antitrypsin variants; current status and SSCP analysis
- Univ. of Toronto, Ontario (Canada)
The serine protease inhibitor {alpha}{sub 1} Antitrypsin ({alpha}{sub 1}AT) is an inhibitor of neutrophil elastase. A deficiency of {alpha}{sub 1}AT (< 20% of the normal amount of {alpha}{sub 1}AT) is associated with early-onset emphysema and childhood liver disease. The most common deficiency allele, PI{sup *}Z, has a frequency of 1-2% in the North American white population. Several rare deficiency alleles (including null (QO) alleles; < 1% of normal) with a combined frequency of approximately 10{sup -4}, have been reported. Of 24 sequenced deficiency variants, the defect in 15 has been proven to be due to gene deletion (2), mRNA degradation (2), error in mRNA processing (1), intracellular protein accumulation (5) and intracellular protein degradation (5). We have determined conditions for detection of new mutations. We have screened DNA from 20 individuals carrying rare deficiency alleles. In some individuals, RFLP haplotype analysis suggested the presence of a new variant. The root alleles, M1 (Ala 213) or M1 (Val 213), and the presence of variants whose mutant sequence alters a restriction endonuclease site were determined by digestion of the amplified exon. Mutation detection was performed by SSCP analysis of each of the four coding exons followed by direct sequencing of the amplified exon. 12 of 14 known mutations (85%) were detected by SSCP analysis. We detected a new null allele in a patient that also carries the QO{sup *}hongkong allele. C to A transversion at the third nucleotide of codon 38 creates a stop codon on the M1(Val 213) root allele. This new variant allele has been named PI{sup *}QOkowloon. Characterization of the mutations leading to {alpha}{sub 1}AT deficiency allows delineation of amino acids critical for stability, for normal secretion and for normal function.
- OSTI ID:
- 134168
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0904
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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