Molecular characterization of the new defective P(brescia) alpha1-antitrypsin allele.

ABSTRACT: Alpha1-antitrypsin (α1AT) deficiency is a hereditary disorder associated with reduced α1AT serum level, predisposing adults to pulmonary emphysema. Among the known mutations of the α1AT gene (SERPINA1) causing α1AT deficiency, a few alleles, particularly the Z allele, may also predispose adults to liver disease. We have characterized a new defective α1AT allele (c.745G>C) coding for a mutant α1AT (Gly225Arg), named Pbrescia. The Pbrescia α1AT allele was first identified in combination with the rare defective Mwürzburg allele in an 11-year-old boy showing significantly reduced serum α1AT level. Subsequently, the Pbrescia allele was found in the heterozygous state with the normal M or the defective Z allele in nine and three adults respectively. In cellular models of the disease, we show that the Pbrescia mutant is retained in the endoplasmic reticulum as ordered polymers and is secreted more slowly than the normal M α1AT. This behaviour recapitulates the abnormal cellular handling and fate of the Z α1AT and suggests that the mutation present in the Pbrescia α1AT causes a conformational change of the protein which, by favouring polymer formation, is etiologic to both severe α1AT deficiency in the plasma and toxic protein-overload in the liver. © 2009 Wiley-Liss, Inc