PMID- 30633749
OWN - NLM
STAT- MEDLINE
DCOM- 20190918
LR  - 20220913
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 14
IP  - 1
DP  - 2019
TI  - Characterisation of a type II functionally-deficient variant of 
      alpha-1-antitrypsin discovered in the general population.
PG  - e0206955
LID - 10.1371/journal.pone.0206955 [doi]
LID - e0206955
AB  - Lung disease in alpha-1-antitrypsin deficiency (AATD) results from dysregulated 
      proteolytic activity, mainly by neutrophil elastase (HNE), in the lung 
      parenchyma. This is the result of a substantial reduction of circulating 
      alpha-1-antitrypsin (AAT) and the presence in the plasma of inactive polymers of 
      AAT. Moreover, some AAT mutants have reduced intrinsic activity toward HNE, as 
      demonstrated for the common Z mutant, as well as for other rarer variants. Here 
      we report the identification and characterisation of the novel AAT reactive 
      centre loop variant Gly349Arg (p.G373R) present in the ExAC database. This AAT 
      variant is secreted at normal levels in cellular models of AATD but shows a 
      severe reduction in anti-HNE activity. Biochemical and molecular dynamics studies 
      suggest it exhibits unfavourable RCL presentation to cognate proteases and 
      compromised insertion of the RCL into beta-sheet A. Identification of a fully 
      dysfunctional AAT mutant that does not show a secretory defect underlines the 
      importance of accurate genotyping of patients with pulmonary AATD manifestations 
      regardless of the presence of normal levels of AAT in the circulation. This 
      subtype of disease is reminiscent of dysfunctional phenotypes in anti-thrombin 
      and C1-inibitor deficiencies so, accordingly, we classify this variant as the 
      first pure functionally-deficient (type II) AATD mutant.
FAU - Laffranchi, Mattia
AU  - Laffranchi M
AUID- ORCID: 0000-0002-0556-6068
AD  - Department of Molecular and Translational Medicine, University of Brescia, 
      Brescia, Italy.
FAU - Elliston, Emma L K
AU  - Elliston ELK
AD  - UCL Respiratory and the Institute of Structural and Molecular Biology, University 
      College London, London, United Kingdom.
FAU - Gangemi, Fabrizio
AU  - Gangemi F
AUID- ORCID: 0000-0001-9389-651X
AD  - Department of Molecular and Translational Medicine, University of Brescia, 
      Brescia, Italy.
FAU - Berardelli, Romina
AU  - Berardelli R
AD  - Department of Molecular and Translational Medicine, University of Brescia, 
      Brescia, Italy.
FAU - Lomas, David A
AU  - Lomas DA
AD  - UCL Respiratory and the Institute of Structural and Molecular Biology, University 
      College London, London, United Kingdom.
FAU - Irving, James A
AU  - Irving JA
AUID- ORCID: 0000-0003-3204-6356
AD  - UCL Respiratory and the Institute of Structural and Molecular Biology, University 
      College London, London, United Kingdom.
FAU - Fra, Annamaria
AU  - Fra A
AUID- ORCID: 0000-0002-4327-3004
AD  - Department of Molecular and Translational Medicine, University of Brescia, 
      Brescia, Italy.
LA  - eng
GR  - MR/N024842/1/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - DH_/Department of Health/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190111
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Mutant Proteins)
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
MH  - Amino Acid Sequence
MH  - *Genetic Variation
MH  - *Genetics, Population
MH  - Humans
MH  - Models, Biological
MH  - Molecular Dynamics Simulation
MH  - Mutant Proteins/chemistry/metabolism
MH  - Protein Domains
MH  - Protein Structure, Secondary
MH  - alpha 1-Antitrypsin/chemistry/*genetics/*metabolism
PMC - PMC6329500
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/01/12 06:00
MHDA- 2019/09/19 06:00
PMCR- 2019/01/11
CRDT- 2019/01/12 06:00
PHST- 2018/10/17 00:00 [received]
PHST- 2019/01/02 00:00 [accepted]
PHST- 2019/01/12 06:00 [entrez]
PHST- 2019/01/12 06:00 [pubmed]
PHST- 2019/09/19 06:00 [medline]
PHST- 2019/01/11 00:00 [pmc-release]
AID - PONE-D-18-30133 [pii]
AID - 10.1371/journal.pone.0206955 [doi]
PST - epublish
SO  - PLoS One. 2019 Jan 11;14(1):e0206955. doi: 10.1371/journal.pone.0206955. 
      eCollection 2019.