αI-Antitrypsin Null(isola di procida)

An αI-antitrypsin deficiency allele caused by deletion of all αI-antitrypsin coding exons

H. Takahashi, R. G. Crystal

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

α1-Antitrypsin (α1AT) deficiency, a common hereditary disorder responsible for emphysema in Caucasians of northern European descent, is caused by single base substitutions, deletions, or additions in the seven exons (I(A)-I(C) and II-V), of the 12.2-kb α1AT gene located on chromosome 14 at q31-32.3. Of the five known representatives of the 'null' group of α1AT-deficiency alleles (α1AT genes incapable of producing α1AT protein detectable in serum) evaluated at the gene level, all result from mutations causing the formation of stop codons in coding exons of the α1AT gene. The present study identifies an α1AT allele (referred to as 'Null(isola di procida)') caused by complete deletion of the α1AT coding exons. The Null(isola di procida) allele was identified in an individual with heterozygous inheritance of M(procida) (an allele associated with α1AT deficiency) and a null allele. Although results of karyotypic analysis were normal, quantification of the copies of α1AT genes in this individual revealed that the index case had only half the normal copies of α1AT genes. Cloning and mapping of the Null(isola di procida) gene demonstrated a deletion of a 17-kb fragment that included exons II-V of the α1AT structural gene. As a consequence of the deletion, the normal noncoding exons (I(A)-I(C)) were followed by exons II-V of the downstream α1AT-like gene. Sequence analysis of the deletion demonstrated a 7-bp repeat sequence (GAGGACA) both 5' to the deletion and at the 3' end of the deletion, a 4-bp palindromic sequence (ACAG vs. CTGT) bracketing the deletion, and a novel inserted 4-bp sequence (CCTG) at the breakpoint, suggesting that the mechanism of the deletion may have been 'slipped mispairing'.

Original languageEnglish
Pages (from-to)403-413
Number of pages11
JournalAmerican Journal of Human Genetics
Volume47
Issue number3
Publication statusPublished - 5 Oct 1990
Externally publishedYes

Fingerprint

Exons
Alleles
Genes
Chromosomes, Human, Pair 14
Terminator Codon
Sequence Deletion
Emphysema
Sequence Analysis
Organism Cloning
Mutation
Serum
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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title = "αI-Antitrypsin Null(isola di procida): An αI-antitrypsin deficiency allele caused by deletion of all αI-antitrypsin coding exons",
abstract = "α1-Antitrypsin (α1AT) deficiency, a common hereditary disorder responsible for emphysema in Caucasians of northern European descent, is caused by single base substitutions, deletions, or additions in the seven exons (I(A)-I(C) and II-V), of the 12.2-kb α1AT gene located on chromosome 14 at q31-32.3. Of the five known representatives of the 'null' group of α1AT-deficiency alleles (α1AT genes incapable of producing α1AT protein detectable in serum) evaluated at the gene level, all result from mutations causing the formation of stop codons in coding exons of the α1AT gene. The present study identifies an α1AT allele (referred to as 'Null(isola di procida)') caused by complete deletion of the α1AT coding exons. The Null(isola di procida) allele was identified in an individual with heterozygous inheritance of M(procida) (an allele associated with α1AT deficiency) and a null allele. Although results of karyotypic analysis were normal, quantification of the copies of α1AT genes in this individual revealed that the index case had only half the normal copies of α1AT genes. Cloning and mapping of the Null(isola di procida) gene demonstrated a deletion of a 17-kb fragment that included exons II-V of the α1AT structural gene. As a consequence of the deletion, the normal noncoding exons (I(A)-I(C)) were followed by exons II-V of the downstream α1AT-like gene. Sequence analysis of the deletion demonstrated a 7-bp repeat sequence (GAGGACA) both 5' to the deletion and at the 3' end of the deletion, a 4-bp palindromic sequence (ACAG vs. CTGT) bracketing the deletion, and a novel inserted 4-bp sequence (CCTG) at the breakpoint, suggesting that the mechanism of the deletion may have been 'slipped mispairing'.",
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