Molecular basis of alpha-1-antitrypsin deficiency

Mark Brantly, Toshihiro Nukiwa, Ronald Crystal

Research output: Contribution to journalArticle

352 Citations (Scopus)

Abstract

Alpha-1-antitrypsin (A1AT) deficiency is an autosomal hereditary disorder associated with a major reduction in serum A1AT levels. Clinically, A1AT deficiency is associated with emphysema in adults and, less commonly, liver disease in neonates. A1AT is a 52-kDa, 394-amino acid, single-chain glycoprotein normally present in serum at 150 to 350 mg/dl. The A1AT gene, composed of seven exons dispersed over 12 kb of chromosomal segment 14q31-32.3, is expressed in heptocytes and mononuclear phagocytes. The A1AT protein, a member of the class of protease inhibitor proteins known as serpins (serine protease inhibitors), is a globular molecule composed of nine alpha-helices and three beta-pleated sheets. The major function of A1AT is to inhibit neutrophil elastase; A1AT does so through an active site centered around Met358 contained within an external stressed loop on the surface of the molecule. A1AT is a highly pleomorphic protein with greater than 75 variants determined at the protein and/or gene level. These variants can be categorized into four groups according to their serum A1AT level and function: normal, deficient, dysfunctional, and absent. There are two important salt bridges within the A1AT molecule (Glu342-Lys290; Glu263-Lys367); a mutation in the A1AT gene causing disruption of either salt bridge causes distinct molecular pathology resulting in reduced serum A1AT levels. Clinically relevant variants can be distinguished by a combination of isoelectric focusing of serum, restriction fragment length analysis of genomic DNA, oligonucleotide probes, and direct sequencing of the variant A1AT genes.

Original languageEnglish
Pages (from-to)13-31
Number of pages19
JournalThe American Journal of Medicine
Volume84
Issue numberSUPPL. 6
DOIs
Publication statusPublished - 24 Jun 1988
Externally publishedYes

Fingerprint

alpha 1-Antitrypsin Deficiency
alpha 1-Antitrypsin
Serum
Autosomal Recessive alpha-1-Antitrypsin Deficiency
Proteins
Salts
Genes
Leukocyte Elastase
Serine Proteinase Inhibitors
Molecular Pathology
Oligonucleotide Probes
DNA Probes
Emphysema
Isoelectric Focusing
Phagocytes
Protease Inhibitors
Liver Diseases
Exons

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Molecular basis of alpha-1-antitrypsin deficiency. / Brantly, Mark; Nukiwa, Toshihiro; Crystal, Ronald.

In: The American Journal of Medicine, Vol. 84, No. SUPPL. 6, 24.06.1988, p. 13-31.

Research output: Contribution to journalArticle

Brantly, Mark ; Nukiwa, Toshihiro ; Crystal, Ronald. / Molecular basis of alpha-1-antitrypsin deficiency. In: The American Journal of Medicine. 1988 ; Vol. 84, No. SUPPL. 6. pp. 13-31.
@article{ec5bad2438124457977c77f033b98564,
title = "Molecular basis of alpha-1-antitrypsin deficiency",
abstract = "Alpha-1-antitrypsin (A1AT) deficiency is an autosomal hereditary disorder associated with a major reduction in serum A1AT levels. Clinically, A1AT deficiency is associated with emphysema in adults and, less commonly, liver disease in neonates. A1AT is a 52-kDa, 394-amino acid, single-chain glycoprotein normally present in serum at 150 to 350 mg/dl. The A1AT gene, composed of seven exons dispersed over 12 kb of chromosomal segment 14q31-32.3, is expressed in heptocytes and mononuclear phagocytes. The A1AT protein, a member of the class of protease inhibitor proteins known as serpins (serine protease inhibitors), is a globular molecule composed of nine alpha-helices and three beta-pleated sheets. The major function of A1AT is to inhibit neutrophil elastase; A1AT does so through an active site centered around Met358 contained within an external stressed loop on the surface of the molecule. A1AT is a highly pleomorphic protein with greater than 75 variants determined at the protein and/or gene level. These variants can be categorized into four groups according to their serum A1AT level and function: normal, deficient, dysfunctional, and absent. There are two important salt bridges within the A1AT molecule (Glu342-Lys290; Glu263-Lys367); a mutation in the A1AT gene causing disruption of either salt bridge causes distinct molecular pathology resulting in reduced serum A1AT levels. Clinically relevant variants can be distinguished by a combination of isoelectric focusing of serum, restriction fragment length analysis of genomic DNA, oligonucleotide probes, and direct sequencing of the variant A1AT genes.",
author = "Mark Brantly and Toshihiro Nukiwa and Ronald Crystal",
year = "1988",
month = "6",
day = "24",
doi = "10.1016/S0002-9343(88)80066-4",
language = "English",
volume = "84",
pages = "13--31",
journal = "American Journal of Medicine",
issn = "0002-9343",
publisher = "Elsevier Inc.",
number = "SUPPL. 6",

}

TY - JOUR

T1 - Molecular basis of alpha-1-antitrypsin deficiency

AU - Brantly, Mark

AU - Nukiwa, Toshihiro

AU - Crystal, Ronald

PY - 1988/6/24

Y1 - 1988/6/24

N2 - Alpha-1-antitrypsin (A1AT) deficiency is an autosomal hereditary disorder associated with a major reduction in serum A1AT levels. Clinically, A1AT deficiency is associated with emphysema in adults and, less commonly, liver disease in neonates. A1AT is a 52-kDa, 394-amino acid, single-chain glycoprotein normally present in serum at 150 to 350 mg/dl. The A1AT gene, composed of seven exons dispersed over 12 kb of chromosomal segment 14q31-32.3, is expressed in heptocytes and mononuclear phagocytes. The A1AT protein, a member of the class of protease inhibitor proteins known as serpins (serine protease inhibitors), is a globular molecule composed of nine alpha-helices and three beta-pleated sheets. The major function of A1AT is to inhibit neutrophil elastase; A1AT does so through an active site centered around Met358 contained within an external stressed loop on the surface of the molecule. A1AT is a highly pleomorphic protein with greater than 75 variants determined at the protein and/or gene level. These variants can be categorized into four groups according to their serum A1AT level and function: normal, deficient, dysfunctional, and absent. There are two important salt bridges within the A1AT molecule (Glu342-Lys290; Glu263-Lys367); a mutation in the A1AT gene causing disruption of either salt bridge causes distinct molecular pathology resulting in reduced serum A1AT levels. Clinically relevant variants can be distinguished by a combination of isoelectric focusing of serum, restriction fragment length analysis of genomic DNA, oligonucleotide probes, and direct sequencing of the variant A1AT genes.

AB - Alpha-1-antitrypsin (A1AT) deficiency is an autosomal hereditary disorder associated with a major reduction in serum A1AT levels. Clinically, A1AT deficiency is associated with emphysema in adults and, less commonly, liver disease in neonates. A1AT is a 52-kDa, 394-amino acid, single-chain glycoprotein normally present in serum at 150 to 350 mg/dl. The A1AT gene, composed of seven exons dispersed over 12 kb of chromosomal segment 14q31-32.3, is expressed in heptocytes and mononuclear phagocytes. The A1AT protein, a member of the class of protease inhibitor proteins known as serpins (serine protease inhibitors), is a globular molecule composed of nine alpha-helices and three beta-pleated sheets. The major function of A1AT is to inhibit neutrophil elastase; A1AT does so through an active site centered around Met358 contained within an external stressed loop on the surface of the molecule. A1AT is a highly pleomorphic protein with greater than 75 variants determined at the protein and/or gene level. These variants can be categorized into four groups according to their serum A1AT level and function: normal, deficient, dysfunctional, and absent. There are two important salt bridges within the A1AT molecule (Glu342-Lys290; Glu263-Lys367); a mutation in the A1AT gene causing disruption of either salt bridge causes distinct molecular pathology resulting in reduced serum A1AT levels. Clinically relevant variants can be distinguished by a combination of isoelectric focusing of serum, restriction fragment length analysis of genomic DNA, oligonucleotide probes, and direct sequencing of the variant A1AT genes.

UR - http://www.scopus.com/inward/record.url?scp=0023898432&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023898432&partnerID=8YFLogxK

U2 - 10.1016/S0002-9343(88)80066-4

DO - 10.1016/S0002-9343(88)80066-4

M3 - Article

VL - 84

SP - 13

EP - 31

JO - American Journal of Medicine

JF - American Journal of Medicine

SN - 0002-9343

IS - SUPPL. 6

ER -