Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis

Abstract

The association between Z α 1 -antitrypsin deficiency and juvenile cirrhosis is well-recognized, and there is now convincing evidence that the hepatic inclusions are the result of entangled polymers of mutant Z α 1 -antitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S α 1 -antitrypsin, which is found in up to 28% of southern Europeans. The S variant is known to have an increased susceptibility to polymerization, although this is marginal compared with the more conformationally unstable Z variant. There has been speculation that the two may interact to produce cirrhosis, but this has never been demonstrated experimentally. This hypothesis was raised again by the observation reported here of a mixed heterozygote for Z α 1 -antitrypsin and another conformationally unstable variant (I α 1 -antitrypsin; 39 Arg→Cys) identified in a 34-year-old man with cirrhosis related to α 1 -antitrypsin deficiency. The conformational stability of the I variant has been characterized, and we have used fluorescence resonance energy transfer to demonstrate the formation of heteropolymers between S and Z α 1 -antitrypsin. Taken together, these results indicate that not only may mixed variants form heteropolymers, but that this can causally lead to the development of cirrhosis.

A Retrospective Study and Gene Analysis of Canine Sterile Panniculitis

“…According to Smith et al, 16% of human patients with sterile panniculitis had α 1 AT deficiency [31], and several mutational phenotypes can result in sterile panniculitis despite a normal serum concentration [4,10]. In fact, there are over 90 genetically recognizable alleles in human, some of which include SNP, deletional, or insertional mutations resulting in enzyme deficiency or altered enzyme function [4,6,10,17]. In the veterinary field, Hughes et al investigated the serum α 1 AT concentration in nine dogs with sterile panniculitis, but could not demonstrate the deficient concentration [12].…”

Diagnosis of α-1-Antitrypsin Deficiency: An Algorithm of Quantification, Genotyping, and Phenotyping

“…In 3 cases, the phenotype assay detected the presence of a rare deficiency allele, the I allele, which was present in conjunction with a Z allele. This finding helped to explain the lower concentrations of A1AT in the serum and to establish a diagnosis of A1AT deficiency (18 ). In certain other cases, the phenotype results indicated the presence of only 1 allele.…”

“…This corresponded to the A1AT concentration, which was Ͻ0.30 g/L in both patients. In 3 of the Z heterozygotes, both the Z and the I allele, which is a partial deficiency allele, were identified by IEF (Table 4), leading to a diagnosis of A1AT deficiency (18 ). For the final Z heterozygote discrepant result, only the M allele was detected by phenotyping, suggesting that the Z allele is not produced or is not released into the circulation at quantities sufficient for detection by the phenotyping assay.…”

“…A number of variations are not associated with a decrease in A1AT quantity or activity and are not linked to any clinical phenotype, for example the M1, M2, G, X, C, and D alleles defined by isoelectric focusing (IEF) migration patterns. There are some rare alleles, however, that are associated with A1AT deficiency, such as the I allele (R63C) (18 ).…”

Prevalence of the serpin peptidase inhibitor (alpha-1-antitrypsin) PI*S and PI*Z alleles in Brazilian children with liver disease

“…Elliot et al (1996) suggest that the PI*S variant has increased susceptibility to polymerization, although this increase is marginal when compared to the PI*Z allele. There has been some speculation regarding synergy between the variants which may lead to cirrhosis in PI*SZ adults (Mahadeva et al, 1999). Hadzic et al (2005) investigated PI*SZ patients and showed that although they had low SERPINA1 levels some of them may have had late hepatic disorders.…”