W. Poller et al., Molecular characterisation of the defective alpha 1-antitrypsin alleles PIMwurzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68lle), EUR J HUM G, 7(3), 1999, pp. 321-331
Deficiency of the serine proteinase inhibitor (serpin) alpha 1-antitrypsin
(alpha 1AT) is the most common autosomal recessive genetic disorder in Nort
hern Europe. alpha 1AT is the physiological regulator of the proteolytic en
zyme neutrophil elastase and severe deficiency states are associated with a
n increased risk of developing chronic obstructive pulmonary disease (COPD)
as a consequence of chronic proteolytic damage to the lungs. Among the kno
wn mutations of the alpha 1AT gene causing severe alpha 1AT deficiency and
COPD a few alleles are also associated with liver disease, When expressed i
n cell cultures, all these particular alleles cause intracellular alpha 1AT
accumulation which appears to be a prerequisite for the development of hep
atic injury, Liver disease is seen in only a small fraction of all patients
carrying such alleles, however. The reason for this is not completely clea
r, but there is evidence that PI ZZ individuals 'susceptible' to liver dise
ase carry an additional defect affecting protein degradation in the endopla
smic reticulum (ER), We characterise a newly identified defective alpha 1AT
allele PI Mwurzburg (Pro369 [(C) under bar CC] to Ser [(T) under bar CC])
associated with a complete intracellular transport block in cell cultures i
n vitro, The allele PI Mheerlen, a previously described different amino aci
d substitution in the same position as PI Mwurzburg (Pro369 [C (C) under ba
r C] to Leu [C (T) under bar C]) is shown to cause complete retention of th
e mutant alpha 1AT in the ER, too, whereas in the recently described mutant
allele PI Q0lisbon (Thr68 [A (C) under bar C] to Ile [A (T) under bar C])
a significantly reduced alpha 1AT secretion from the cells was observed. Ad
enovirus-mediated recombinant expression of mutant Mwurzburg and Mheerlen,
and of wild-type alpha 1AT in mouse liver in vivo showed that the mutant hu
man proteins were not secreted into the mouse plasma, in contrast with huma
n wild-type alpha 1AT which circulated at high concentrations over several
weeks, In summary, all transportation deficient alpha 1ATs analysed have th
e potential to cause lung disease in the homozygous state or in heterozygou
s carriers of another deficiency allele, and they may also cause liver dise
ase in certain patients, The mutant PI Mwurzburg and Mheerlen alpha 1ATs ar
e completely retained within synthesising cells, and the molecular defect o
f transportation in these two alleles may be similar to that in the common
PI Z allele. The molecular defect in the PI Q0lisbon allele (Thr68Ile) show
s similarity with the immediately neighbouring Mmineral springs mutation (G
ly67Glu).