No abstract

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.

No abstract

In three patients with monoclonal gammopathies: a case of multiple myeloma, a case of monoclonal gammopathy of uncertain significance (MGUS) and a case of monoclonal gammopathy associated with lymphocytic lymphoma, we found the presence of a circulating lupus-like anticoagulant. Coagulative studies showed that the paraproteins: an IgG3k, an IgG1k and an IgMlambda, were responsible for the anticoagulant activity by interacting with the thromboplastin phospholipids. Using isoelectrofocusing we demonstrated that the three monoclonal immunoglobulins had a strong basic charge which may have contributed to determining their interaction with the acidic thromboplastin phospholipids. The binding of various phospholipids to the monoclonal proteins was assessed by the fluorescence quenching method which showed heterogeneous specificity. In order to establish whether the electrical charge is also relevant in cases with polyclonal lupus anticoagulant, the polyclonal immunoglobulins were fractionated according to their charge. The strongest inhibitor activity was found in the most basic immunoglobulins. Monoclonal lupus-like anticoagulants represent useful tools for investigating the heterogeneous world of polyclonal lupus-like anticoagulants.

No abstract