Molecular characterization of the new defective Pbrescia alpha1-antitrypsin allele

✍ Scribed by Daniela Medicina; Nadia Montani; Anna M. Fra; Laura Tiberio; Luciano Corda; Elena Miranda; Alessandro Pezzini; Fausta Bonetti; Rosaria Ingrassia; Roberta Scabini; Fabio Facchetti; Luisa Schiaffonati

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 434 KB
• Volume: 30
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.21043

✦ Synopsis

Alpha1-antitrypsin (α 1 AT) deficiency is a hereditary disorder associated with reduced α 1 AT serum level, predisposing adults to pulmonary emphysema. Among the known mutations of the α 1 AT gene (SERPINA1) causing α 1 AT deficiency, a few alleles, particularly the Z allele, may also predispose adults to liver disease. We have characterized a new defective α 1 AT allele (c.745G>C) coding for a mutant α 1 AT (Gly225Arg), named P brescia . The P brescia α 1 AT allele was first identified in combination with the rare defective M würzburg allele in an 11-year-old boy showing significantly reduced serum α 1 AT level. Subsequently, the P brescia 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 P brescia mutant is retained in the endoplasmic reticulum as ordered polymers and is secreted more slowly than the normal M α 1 AT. This behaviour recapitulates the abnormal cellular handling and fate of the Z α 1 AT and suggests that the mutation present in the P brescia α 1 AT causes a conformational change of the protein which, by favouring polymer formation, is etiologic to both severe α 1 AT deficiency in the plasma and toxic protein-overload in the liver.