PMID- 32515985
OWN - NLM
STAT- MEDLINE
DCOM- 20201123
LR  - 20201123
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Linking)
VI  - 63
IP  - 4
DP  - 2020 Oct
TI  - New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing 
      Alpha-1 Antitrypsin Deficiency.
PG  - 444-451
LID - 10.1165/rcmb.2020-0021OC [doi]
AB  - Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by 
      reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A 
      member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient 
      alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we 
      describe two new alleles carrying an S mutation but producing a null phenotype: 
      QO(Vigo) and QO(Aachen). The new alleles were identified by sequencing the 
      SERPINA1 gene in three patients who had lower AAT serum levels than expected for 
      the initial genotype. These alleles are the result of combined mutations in cis 
      in a PI*S allele. Sequencing detected the S mutation in cis with Tyr138Cys 
      (S+Tyr138Cys) in two patients, whereas a third one had the S mutation in cis with 
      Pro391Thr variant (S+Pro391Thr). When expressed in a cellular model, these 
      variants caused strong AAT polymerization and very low AAT secretion to almost 
      undetectable levels. The isoelectric focusing method for plasma AAT phenotyping 
      did not show AAT protein encoded by the novel mutant alleles, behaving as null. 
      We called these alleles PI*S-plus because the S variant was phased with another 
      variant conferring more aggressive characteristics to the allele. The current 
      data demonstrate that the clinical variability observed in AATD can be explained 
      by additional genetic variation, such as dual cis-acting variants in the SERPINA1 
      gene. The possible existence of other unrevealed variants combined in the PI*S 
      alleles should be considered to improve the genetic diagnosis of the patients.
FAU - Matamala, Nerea
AU  - Matamala N
AD  - Molecular Genetics Unit, Instituto de Investigacion de Enfermedades Raras, 
      Instituto de Salud Carlos III, Madrid, Spain.
FAU - Gomez-Mariano, Gema
AU  - Gomez-Mariano G
AD  - Molecular Genetics Unit, Instituto de Investigacion de Enfermedades Raras, 
      Instituto de Salud Carlos III, Madrid, Spain.
FAU - Perez, Jose Antonio
AU  - Perez JA
AD  - Area de Genetica, Instituto Universitario de Enfermedades Tropicales y Salud 
      Publica de Canarias, Universidad de La Laguna, Tenerife, Spain.
FAU - Baladron, Beatriz
AU  - Baladron B
AD  - Molecular Genetics Unit, Instituto de Investigacion de Enfermedades Raras, 
      Instituto de Salud Carlos III, Madrid, Spain.
FAU - Torres-Duran, Maria
AU  - Torres-Duran M
AD  - Servicio de Neumologia, Hospital Alvaro Cunqueiro, Estructura Organizativa de 
      Xestion Integrada Vigo, Pneumovigo I + i, Instituto de Investigacion Sanitaria 
      Galicia Sur, Vigo, Spain.
FAU - Michel, Francisco Javier
AU  - Michel FJ
AD  - Servicio de Neumologia, and.
FAU - Saez, Raquel
AU  - Saez R
AD  - Genetica e Inmunologia, Hospital Universitario Donostia, Pais Vasco, Spain.
FAU - Hernandez-Perez, Jose Maria
AU  - Hernandez-Perez JM
AD  - Servicio de Neumologia, Hospital General de la Palma, Canarias, Spain.
FAU - Belmonte, Irene
AU  - Belmonte I
AD  - Biochemistry Department, Hospital Vall d'Hebron, Barcelona, Spain.
FAU - Rodriguez-Frias, Francisco
AU  - Rodriguez-Frias F
AD  - Biochemistry Department, Hospital Vall d'Hebron, Barcelona, Spain.
FAU - Blanco, Ignacio
AU  - Blanco I
AD  - Registro Espanol de Pacientes con Deficit de Alfa-1 Antitripsina, Fundacion 
      Espanola, de Pulmon, Respira, Sociedad Espanola de Neumologia y Cirugia Toracica, 
      Barcelona, Spain.
FAU - Strnad, Pavel
AU  - Strnad P
AD  - Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany.
FAU - Janciauskiene, Sabina
AU  - Janciauskiene S
AD  - Department of Respiratory Medicine, Biomedical Research in Endstage and 
      Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, 
      Hannover Medical School, Hannover, Germany; and.
FAU - Martinez-Delgado, Beatriz
AU  - Martinez-Delgado B
AUID- ORCID: 0000-0001-6834-350X
AD  - Molecular Genetics Unit, Instituto de Investigacion de Enfermedades Raras, 
      Instituto de Salud Carlos III, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
CIN - Am J Respir Cell Mol Biol. 2020 Oct;63(4):403-404. PMID: 32716630
MH  - Adult
MH  - Alleles
MH  - DNA Mutational Analysis/methods
MH  - Female
MH  - Gene Frequency/genetics
MH  - Genotype
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Mutation/*genetics
MH  - Phenotype
MH  - alpha 1-Antitrypsin/*genetics
MH  - alpha 1-Antitrypsin Deficiency/*genetics
OTO - NOTNLM
OT  - PI*S allele
OT  - SERPINA1 genetic mutations
OT  - alpha-1 antitrypsin
OT  - polymerization
EDAT- 2020/06/10 06:00
MHDA- 2020/11/24 06:00
CRDT- 2020/06/10 06:00
PHST- 2020/06/10 06:00 [pubmed]
PHST- 2020/11/24 06:00 [medline]
PHST- 2020/06/10 06:00 [entrez]
AID - 10.1165/rcmb.2020-0021OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2020 Oct;63(4):444-451. doi: 10.1165/rcmb.2020-0021OC.