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

Human Mutation
Daniela MedicinaLuisa Schiaffonati


Alpha1-antitrypsin (alpha(1)AT) deficiency is a hereditary disorder associated with reduced alpha(1)AT serum level, predisposing adults to pulmonary emphysema. Among the known mutations of the alpha(1)AT gene (SERPINA1) causing alpha(1)AT deficiency, a few alleles, particularly the Z allele, may also predispose adults to liver disease. We have characterized a new defective alpha(1)AT allele (c.745G>C) coding for a mutant alpha(1)AT (Gly225Arg), named P(brescia). The P(brescia) alpha(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 alpha(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 alpha(1)AT. This behaviour recapitulates the abnormal cellular handling and fate of the Z alpha(1)AT and suggests that the mutation present in the P(brescia) alpha(1)AT causes a conformational change of the protein which, by favouring polymer formation, is eti...Continue Reading


Nov 27, 2014·Orphanet Journal of Rare Diseases·Ilaria FerrarottiMaurizio Luisetti
Dec 10, 2015·Human Molecular Genetics·Riccardo RonzoniAnna Maria Fra
Jun 29, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Elena MirandaDavid A Lomas
Jan 1, 2014·Trends in Molecular Medicine·Bibek GooptuDavid A Lomas
Mar 15, 2018·Human Molecular Genetics·Mattia LaffranchiAnnamaria Fra
Apr 9, 2011·Respiration; International Review of Thoracic Diseases·Luciano CordaBruno Balbi
Feb 6, 2016·The European Respiratory Journal·Annamaria FraElena Miranda
Apr 2, 2021·The Application of Clinical Genetics·Susana Seixas, Patricia Isabel Marques
Jun 3, 2021·International Journal of Molecular Sciences·Riccardo RonzoniAnnamaria Fra
Aug 20, 2021·Therapeutic Advances in Chronic Disease·Kimberly E Foil

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