The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote

BMC Pulmonary Medicine

Robert Andrew Stockley¹  Firas Koura²  Nicola Jane Sinden³ 

[1]Lung Function and Sleep Department, ADAPT Office (Office 4) Queen Elizabeth Hospital, Birmingham B15 2WB, UK

[2]Kentucky Lung Clinic, Hazard, KY, USA

[3]Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK

关键词: Serpin;    Proteinases;    Emphysema;    Alpha-1-antitrypsin deficiency;   

Others  :  1109553
DOI  :  10.1186/1471-2466-14-132

 received in 2014-05-14, accepted in 2014-07-29,  发布年份 2014

【 摘 要 】

Background

Inheritance of the F variant of alpha-1-antitrypsin is associated with normal circulating protein levels, but it is believed to be dysfunctional in its ability to inhibit neutrophil elastase and therefore has been implicated as a susceptibility factor for the development of emphysema. In this study, its functional characteristics were determined following the identification of a unique patient with the PiFF phenotype, and the implications as a susceptibility factor for emphysema are considered both in homozygotes and heterozygotes.

Methods

Second order association rate constants were measured for M, Z, S and F variants of alpha-1-antitrypsin with neutrophil elastase and proteinase 3. Clinical characteristics of the PiFF homozygote and six PiFZ heterozygote subjects were studied.

Results

The F variant had a reduced association rate constant with neutrophil elastase (5.60 ± 0.83 × 10⁶ M^-1 s^-1) compared to the normal M variant (1.45 ± 0.02 × 10⁷ M^-1 s^-1), indicating an increased time to inhibition that was comparable to that of the Z variant (7.34 ± 0.03 × 10⁶ M^-1 s^-1). The association rate constant for the F variant and proteinase 3 (1.06 ± 0.22 × 10⁶ M^-1 s^-1) was reduced compared to that with neutrophil elastase, but was similar to that of other alpha-1-antitrypsin variants. Of the six PiFZ heterozygotes, five had airflow obstruction and radiological evidence of emphysema. The PiFF homozygote had airflow obstruction but no emphysema. None of the patients had clinical evidence of liver disease.

Conclusions

The F variant may increase susceptibility to elastase-induced lung damage but not emphysema, whereas co-inheritance with the Z deficiency allele may predispose to emphysema despite reasonable plasma concentrations of alpha-1-antitrypsin.

【 授权许可】

   
2014 Sinden et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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