Premium
Molecular characterization of the new defective P brescia alpha1‐antitrypsin allele
Author(s) -
Medicina Daniela,
Montani Nadia,
Fra Anna M.,
Tiberio Laura,
Corda Luciano,
Miranda Elena,
Pezzini Alessandro,
Bonetti Fausta,
Ingrassia Rosaria,
Scabini Roberta,
Facchetti Fabio,
Schiaffonati Luisa
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21043
Subject(s) - allele , biology , alpha 1 antitrypsin deficiency , mutant , endoplasmic reticulum , gene , mutation , genetics , compound heterozygosity , mutant protein , microbiology and biotechnology , immunology
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. © 2009 Wiley‐Liss, Inc.