PMID- 36496391
OWN - NLM
STAT- MEDLINE
DCOM- 20221216
LR  - 20221220
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Print)
IS  - 1465-9921 (Linking)
VI  - 23
IP  - 1
DP  - 2022 Dec 10
TI  - New variants of alpha-1-antitrypsin: structural simulations and clinical 
      expression.
PG  - 339
LID - 10.1186/s12931-022-02271-8 [doi]
LID - 339
AB  - BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is characterized by reduced 
      serum levels of the AAT protein and predisposes to liver and lung disease. The 
      characterization at structural level of novel pathogenic SERPINA1 mutants coding 
      for circulating AAT could provide novel insights into the mechanisms of AAT 
      misfolding. The present study aimed to provide a practical framework for the 
      identification and analysis of new AAT mutations, combining structural 
      simulations and clinical data. METHODS: We analysed a total of five mutations 
      (four not previously described) in a total of six subjects presenting moderate to 
      severe AATD: Gly95Alafs*18, Val210Glu, Asn247Ser, Pi*S + Asp341His and 
      Pi*S + Leu383Phe + Lys394Ile. Clinical data, genotyping and phenotyping assays, 
      structural mapping, and conformational characterization through molecular dynamic 
      (MD) simulations were developed and combined. RESULTS: Newly discovered AAT 
      missense variants were localized both on the interaction surface and the 
      hydrophobic core of the protein. Distribution of mutations across the structure 
      revealed Val210Glu at the solvent exposed s4C strand and close to the "Gate" 
      region. Asn247Ser was located on the accessible surface, which is important for 
      glycan attachment. On the other hand, Asp341His, Leu383Phe were mapped close to 
      the "breach" and "shutter" regions. MD analysis revealed the reshaping of local 
      interactions around the investigated substitutions that have varying effects on 
      AAT conformational flexibility, hydrophobic packing, and electronic surface 
      properties. The most severe structural changes were observed in the double- and 
      triple-mutant (Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile) molecular 
      models. The two carriers presented impaired lung function. CONCLUSIONS: The 
      results characterize five variants, four of them previously unknown, of the 
      SERPINA1 gene, which define new alleles contributing to the deficiency of AAT. 
      Rare variants might be more frequent than expected, and therefore, in discordant 
      cases, standardized screening of the S and Z alleles needs complementation with 
      gene sequencing and structural approaches. The utility of computational modelling 
      for providing supporting evidence of the pathogenicity of rare single nucleotide 
      variations is discussed.
CI  - (c) 2022. The Author(s).
FAU - Gonzalez, Angel
AU  - Gonzalez A
AD  - Department of Computational Medicine, Statistic Unit, Medicine Faculty, 
      Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain.
FAU - Belmonte, Irene
AU  - Belmonte I
AD  - Department of Clinical Biochemistry, Hospital Universitari Vall d'Hebron, Vall 
      d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
FAU - Nunez, Alexa
AU  - Nunez A
AD  - Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron 
      Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, P. Vall 
      d'Hebron 119-129, 08035, Barcelona, Spain.
FAU - Farago, Georgina
AU  - Farago G
AD  - Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron 
      Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, P. Vall 
      d'Hebron 119-129, 08035, Barcelona, Spain.
FAU - Barrecheguren, Miriam
AU  - Barrecheguren M
AD  - Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron 
      Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, P. Vall 
      d'Hebron 119-129, 08035, Barcelona, Spain.
FAU - Pons, Monica
AU  - Pons M
AD  - Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, 
      Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital 
      Campus, Barcelona, Spain.
FAU - Orriols, Gerard
AU  - Orriols G
AD  - Department of Clinical Biochemistry, Hospital Universitari Vall d'Hebron, Vall 
      d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
FAU - Gabriel-Medina, Pablo
AU  - Gabriel-Medina P
AD  - Department of Clinical Biochemistry, Hospital Universitari Vall d'Hebron, Vall 
      d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
FAU - Rodriguez-Frias, Francisco
AU  - Rodriguez-Frias F
AD  - Department of Clinical Biochemistry, Hospital Universitari Vall d'Hebron, Vall 
      d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
AD  - Facultat de Medicina, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, 
      Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, 
      (CIBEREHD), Barcelona, Spain.
AD  - Clinical Biochemistry Research Group/Vall d'Hebron Institut de Recerca (VHIR), 
      Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
FAU - Miravitlles, Marc
AU  - Miravitlles M
AD  - Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron 
      Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, P. Vall 
      d'Hebron 119-129, 08035, Barcelona, Spain. marcm@separ.es.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias (CIBERES), 
      Barcelona, Spain. marcm@separ.es.
FAU - Esquinas, Cristina
AU  - Esquinas C
AD  - Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron 
      Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, P. Vall 
      d'Hebron 119-129, 08035, Barcelona, Spain.
AD  - Public Health, Mental, Maternal and Child Health Nursing Departament, Faculty of 
      Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
LA  - eng
PT  - Journal Article
DEP - 20221210
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
MH  - Humans
MH  - *alpha 1-Antitrypsin/genetics
MH  - *alpha 1-Antitrypsin Deficiency/diagnosis/genetics
MH  - Alleles
MH  - Mutation/genetics
PMC - PMC9741788
OTO - NOTNLM
OT  - Alpha-1 antitrypsin deficiency
OT  - Molecular dynamic simulations
OT  - SERPINA1 novel variants
OT  - Structural mapping
COIS- Cristina Esquinas has received speaker fees from CSL Behring. Marc Miravitlles 
      has received speaker or consulting fees from AstraZeneca, Boehringer Ingelheim, 
      Chiesi, Cipla, CSL Behring, Kamada, GlaxoSmithKline, Grifols, Menarini, Mereo 
      Biopharma, Novartis, pH Pharma, Palobiofarma SL, TEVA, Spin Therapeutics, 
      Speciality Therapeutics, Jansen, and Zambon, and research grants from Grifols. 
      Miriam Barrecheguren has received speaker fees from Grifols, Menarini, CSL 
      Behring, GSK and consulting fees from GSK, Novartis, Boehringer Ingelheim and 
      Gebro Pharma. The remaining authors report no conficts of interest.
EDAT- 2022/12/11 06:00
MHDA- 2022/12/15 06:00
PMCR- 2022/12/10
CRDT- 2022/12/10 23:18
PHST- 2022/03/29 00:00 [received]
PHST- 2022/12/01 00:00 [accepted]
PHST- 2022/12/10 23:18 [entrez]
PHST- 2022/12/11 06:00 [pubmed]
PHST- 2022/12/15 06:00 [medline]
PHST- 2022/12/10 00:00 [pmc-release]
AID - 10.1186/s12931-022-02271-8 [pii]
AID - 2271 [pii]
AID - 10.1186/s12931-022-02271-8 [doi]
PST - epublish
SO  - Respir Res. 2022 Dec 10;23(1):339. doi: 10.1186/s12931-022-02271-8.