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Alpha-1-Antitrypsin
Reverse hybridisation assay for the determination
of the point mutations PiZ and PiS in the human gene for alpha-1-antitrypsin
RDB2010
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lpha-1-Antitrypsin (Pi) is
a protease inhibitor, the lack of which is associated with pulmonary
and hepatic diseases. The Pi gene is located on the long distal arm
of the Chromosome14. With an incidence of 1:1600 the lack of alpha-1-antitrypsin
is one of the most frequent hereditary diseases. It is transmitted
recessively. The pathogenesis is still unclear, since not all carriers
manifest the illness. The results of investigations with twin pairs
suggest an influence of exogeneous factors.
Up to 25% of the children with total lack of alpha-1-antitrypsin (homozygous
PiZ mutation) develop a cirrhosis of the liver, while about 75% of
all adults concerned develop obstructive lung diseases.
PiZ is by far the most frequent of the deficiency alleles with clinical
significance. The also frequent PiS allele seems to be relevant only
in combination with the PiZ allele. Carriers of PiS alone normally
do not get ill.
Heterozygous carriers of PiMZ or PiSZ normally are clinically inconspicious
or, with the exception of smokers, only develop a mild form of the
illness. Heterozygous carriers who smoke in most cases develop chronical
obstructive lung diseases comparable to the symptoms seen in homozygous
non-smoking carriers.
The diagnosis is effected by determining the level of alpha-1-antitrypsin
in the blood. A significantly diminished concentration of this protein
points to homozygositiy of the defect. Heterozygous carriers of the
defect mutation show concentrations in the lower region of the normal
range. Since alpha-1-antitrypsin is an acute phase protein, even heterozygous
carriers may show a slightly increased level during infections or
under therapy with estrogens or other steroids. The determination
of the alpha-1-antitrypsin level in the blood therefore is unsuitable
for the detection of heterozygous carriers. Only the typing of the
alpha-1-antitrypsin alleles allows a diagnostic statement.
With the alpha-1-antitrypsin assay from AID homo- and heterozygous
carriers can be unmistakably detected and differentiated. Other, mostly
irrelevant alleles are not taken into account.
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References
Eriksson, S. G.
Liver disease in a 1-antitrypsin deficiency.
Scand. J. Gastroenterol. 20: 907 (1985)
Janus, E. D., Phillips, N. T., Carrel, R. W.
Smoking, lung function and a 1-antitrypsin deficiency.
Lancet 1: 152 (1985)
Braun, A., Meyer, P., Cleve, H., Roscher, A. A.
Rapid and simple diagnosis of the two common a 1-proteinase
inhibitor deficiency alleles PiZ and PiS by DNA analysis.
Eur. J. Clin. Chem. Clin. Biochem. 34: 761 (1996)
Zuntar, I., Topic, E., Jurcic, Z., Cekada, S.
Genotyping of a1-Antitrypsin S and Z Alleles
Clin. Lab. 44: 837-843 (1998) |
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