Search

Genetic alpha-1-antitrypsin (AAT) deficiency may be due to defective secretion, intracellular degradation, or lack of synthesis. Defective secretion results in hepatocytic storage and liver disease. These two events occur only with the common deficiency variant, Z AAT, and with a few rare deficiency variants, called M-like. Hepatocytic storage of AAT (either Z or M-like) can be demonstrated in tissue sections by specific immunostaining with a polyclonal anti-AAT antibody, that recognizes all variants of AAT. A monoclonal antibody capable of selectively and exclusively reacting with Z AAT has been generated and successfully used in both serum and tissue studies.To determine whether a new M-like variant, M Cagliari, carries a mutation different from Z AAT, we have compared antigenic properties and DNA sequences of the two variants. Liver tissue sections from PiZ and PiM Cagliari patients were stained with both polyclonal anti-AAT and monoclonal anti-Z AAT antibodies. DNAs were polymerase chain reaction-amplified with AAT-specific primers and sequenced.Liver tissue sections from PiZ livers were positively stained with either the polyclonal or the monoclonal antibody. The PiM Cagliari liver sections reacted with the polyclonal antibody, but not with the monoclonal anti-Z AAT, thus indicating a difference in antigenicity from Z AAT. Accordingly, DNA analysis ruled out a Z mutation and revealed a microdeletion in exon II, identical with M Malton.A simple immunohistochemical assay based upon the application of both polyclonal and monoclonal antibodies represents a reliable test to distinguish Z and nonZ AAT deficiencies, thus assisting in the selection of cases worthy of more time-consuming analyses such as DNA sequencing. The same approach may be used for the characterization of as yet undefined PiM cases with AAT liver storage.

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked humeroperoneal dystrophy associated with cardiomyopathy that is distinct from the Duchenne and Becker forms of X-linked muscular dystrophy. Linkage analysis has assigned EDMD to the terminal region of the human X chromosome long arm. We report here further linkage analysis in two multigenerational EDMD families using seven Xq28 marker loci. Cumulative lod scores suggest that EDMD is approximately 2 cM from DXS52 (lod = 15.67) and very close to the factor VIII (F8C) and the red/green color pigment (R/GCP) loci, with respective lod scores of 9.62 and 10.77, without a single recombinant. Several recombinations between EDMD and three proximal Xq28 markers suggest that the EDMD gene is located in distal Xq28. Multipoint linkage analysis indicates that the odds are 2,000:1 that EDMD lies distal to DXS305. These data substantially refine the ability to perform accurate carrier detection, prenatal diagnosis, and the presymptomatic diagnosis of at-risk males for EDMD by linkage analysis. The positioning of the EDMD locus close to the loci for F8C and R/GCP will assist in future efforts to identify and isolate the disease gene.