| Pubmed | emedicine | OMIM | NORD | Web | Ggl Images | Yho Images | Videos |

alpha1-anti-trypsine deficiency

MIM.107400 14q32.1

AAT deficiency, PI1 deficiency

 

Deficiency of alpha1-antitrypsin was clinically described for the first time in 1963 by Carl-Bertil Laurell and Sten Eriksson, who noted an absence of the alpha1-band on electrophoresis of the serum of some patients with lung disease.

More then 70 naturally occurring variants of alpha1-antitrypsin have been described and characterized by their migration on isolelectric focusing gels.

Pathogenesis

One in 2,000 individuals from northern Europe is homozygous for the severe Z mutation (a E342K substitution), with plasma levels that are 10-15% of those present in individuals with the normal M allele.

The Z mutation results in the accumulation of alpha1-antitrypsin as PAS-positive inclusions in the rough endoplasmic reticulum of the liver.

These inclusions cause transient juvenile hepatitis in 90% of homozygotes; 1-2% of these individuals will also develop cirrhosis and be at risk of developing hepatocellular carcinoma.

The main function of alpha1-antitrypsin is to protect the tissues, and especially the elastic tissue of the lungs, against the enzyme neutrophil elastase. The lack of circulating alpha1-antitrypsin results in an imbalance between enzymes and inhibitors in the lung, which causes early-onset panlobular emphysema.

-  The Z mutation in alpha1-antitrypsin is a glutamic acid to lysine substitution at residue P17 (17 residues proximal to the P1 residue of the reactive-centre loop) at the head of strand five of -sheet A and at the base of the mobile reactive loop. The mutation is in a crucial mobile domain of alpha1-antitrypsin - the hinge between beta-sheet A and the peptide loop that contains the reactive centre.

As a result of this mutation, beta-sheet A opens, so allowing the reactive loop to insert partially into the top of the central strand in beta-sheet A.

This insertion into the top of the sheet leaves the bottom-half open and therefore ready to accept the reactive loop of another alpha1-antitrypsin molecule.

Most of the newly synthesized misfolded form will be eliminated but the remainder proceeds through the endoplasmic pathway.

Here, sequential intermolecular loop-sheet linkages occur with the formation of long chain polymers. It is the entanglement of these polymers in the final stages of the endoplasmic pathway of the hepatocyte that results in the large inclusion bodies that are apparent on light microscopy.

Support for the occurrence of this polymerization comes from the demonstration that Z alpha1-antitrypsin forms chains of polymers when incubated under physiological conditions in vitro. The rate was accelerated by raising the temperature to 41 °C and could be blocked by peptides that compete with the loop to anneal to beta-sheet A.

The role of polymerization in vivo was clarified by the demonstration of alpha1-antitrypsin polymers in inclusion bodies from the liver of a Z alpha1-antitrypsin homozygote with cirrhosis and in hepatoma cell lines that express the Z variant.

Moreover, point mutations that block polymerization increased the secretion of mutants of alpha1-antitrypsin from a Xenopus oocyte expression system.

It seems likely that the rate at which Z alpha1-antitrypsin polymers are degraded in the endoplasmic reticulum will determine the degree of cytotoxicity and hence explain why children with the same point mutation have different risks of liver disease.

See also

-  conformational diseases

References

-  Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet. 2002 Oct;3(10):759-68. PMID: #12360234#

-  Carrell RW, Lomas DA. Alpha1-antitrypsin deficiency--a model for conformational diseases. N Engl J Med. 2002 Jan 3;346(1):45-53. PMID: #11778003#



Forum de l'article

Contact us at humpath2004@yahoo.ca if you want to be the curator of this page or this section.
Copyright www.humpath.com