PMID- 33150777
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220420
IS  - 2372-952X (Print)
IS  - 2372-952X (Electronic)
IS  - 2372-952X (Linking)
VI  - 8
IP  - 1
DP  - 2021 Jan
TI  - The Clinical Utility of Determining the Allelic Background of Mutations Causing 
      Alpha-1 Antitrypsin Deficiency: The Case with the Null Variant 
      Q0(Mattawa)/Q0(Ourem).
PG  - 31-40
LID - 10.15326/jcopdf.8.1.2020.0168 [doi]
AB  - BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is caused by genetic variants 
      in the SERPINA1 gene conferring risk of developing emphysema. The clinical 
      expression of AATD-related emphysema mostly occurs in carriers of 2 deficient 
      alleles. By DNA sequencing of SERPINA1, numerous rare variants have been 
      identified. Clarifying whether 2 mutations observed in 1 patient are on the same 
      or distinct alleles has obvious clinical implications. METHODS: We studied 7 
      carriers of a rare variant, Leu353Phe_fsTer24, known to lead to undetectable 
      serum levels of AAT. Two of them were also carriers of the S or Z allele. We 
      developed an allele-specific DNA sequencing method to characterize the allelic 
      background of the Leu353Phe_fsTer24 variant. RESULTS: The Leu353Phe_fsTer24 
      variant was transmitted on the same allele as the M3 variant (E376D) in all 
      patients. This mutation is thus named Q0(Ourem) on the conventional PI system. We 
      demonstrated that individuals harboring the E264V (S) and E342K (Z) mutations had 
      them on distinct alleles from Q0(Ourem) and are, thus, compound heterozygotes. 
      The 7 Q0(Ourem) carriers had AAT levels ranging from 0.18g/l to 0.82g/l. The 
      lowest AAT serum levels were observed in compound heterozygotes (S/Q0(Ourem) and 
      Z/Q0(Ourem)) suggesting higher risk of developing emphysema. CONCLUSION: For the 
      7 patients, Leu353Phe_fsTer24 is transmitted on the M3 background and they are, 
      thus, carriers of the Q0(Ourem) allele. Allele-specific DNA sequencing was useful 
      to distinguish 1 or 2 deficient alleles in carriers of 2 mutations. In rare 
      cases, this method is important to understand the clinical significance of 
      genetic variants found in SERPINA1.
CI  - JCOPDF (c) 2021.
FAU - Bellemare, Judith
AU  - Bellemare J
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec - Universite 
      Laval, Quebec, QC, Canada.
FAU - Gaudreault, Nathalie
AU  - Gaudreault N
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec - Universite 
      Laval, Quebec, QC, Canada.
FAU - Valette, Kim
AU  - Valette K
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec - Universite 
      Laval, Quebec, QC, Canada.
FAU - Belmonte, Irene
AU  - Belmonte I
AD  - Pneumology Department, Hospital Universitari Vall d Hebron, Vall d Hebron 
      Institut de Recerca (VHIR), 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, 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, Barcelona, 
      Spain.
AD  - CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
FAU - Maltais, Francois
AU  - Maltais F
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec - Universite 
      Laval, Quebec, QC, Canada.
FAU - Bosse, Yohan
AU  - Bosse Y
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec - Universite 
      Laval, Quebec, QC, Canada.
AD  - Department of Molecular Medicine, Laval University, Quebec City, Canada.
LA  - eng
GR  - la Fondation JD Begin de l'Universite Laval/Canada
GR  - the Fondation de l'Institut universitaire de cardiologie et de pneumologie de 
      Quebec/Canada
GR  - MOP - 123369/CAPMC/CIHR/Canada
GR  - Grifols/United States
PT  - Journal Article
PL  - United States
TA  - Chronic Obstr Pulm Dis
JT  - Chronic obstructive pulmonary diseases (Miami, Fla.)
JID - 101635411
PMC - PMC8047621
OTO - NOTNLM
OT  - Alpha-1 antitrypsin deficiency
OT  - Q0(ourem)
OT  - allele-specific DNA sequencing
OT  - null variants
COIS- Marc Miravitlles has received speaker fees from AstraZeneca, Boehringer 
      Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Zambon, CSL Behring, Grifols and 
      Novartis, consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, 
      GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, 
      Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis and Grifols and 
      research grants from GlaxoSmithKline and Grifols. Francois Maltais received fees 
      for speaking at conferences sponsored by Boehringer Ingelheim, Novartis and 
      Grifols; research grants for participating in multicenter trials sponsored by 
      GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Sanofi, and Novartis; and 
      unrestricted research grants from Boehringer Ingelheim, Novartis and Grifols. 
      Yohan Bosse received speaker fees from Grifols Canada, Ltd. All other authors 
      have nothing to declare.
EDAT- 2020/11/06 06:00
MHDA- 2020/11/06 06:01
PMCR- 2021/01/25
CRDT- 2020/11/05 06:14
PHST- 2020/11/06 06:00 [pubmed]
PHST- 2020/11/06 06:01 [medline]
PHST- 2020/11/05 06:14 [entrez]
PHST- 2021/01/25 00:00 [pmc-release]
AID - 10.15326/jcopdf.8.1.2020.0168 [doi]
PST - ppublish
SO  - Chronic Obstr Pulm Dis. 2021 Jan;8(1):31-40. doi: 10.15326/jcopdf.8.1.2020.0168.