New cis -acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency

American Journal of Respiratory Cell and Molecular Biology
Nerea MatamalaBeatriz Martínez-Delgado

Abstract

Alpha-1 Antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum Alpha-1 Antitrypsin (AAT) due to mutations in the SERPINA1 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 S mutation, but producing null phenotype: QOVigo and QOAachen. The new alleles were identified by sequencing 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, while 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. 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 as PI*S-plus because the S variant was phased with another variant conferring more aggressive characteristics to the allele. The current data demons...Continue Reading

References

Dec 1, 1989·Trends in Genetics : TIG·R G Crystal
Jun 24, 1988·The American Journal of Medicine·M BrantlyR G Crystal
Jul 22, 1998·Journal of Clinical Laboratory Analysis·T B MartinsH R Hill
Mar 27, 1999·The Journal of Biological Chemistry·T R DaffornD A Lomas
Apr 9, 1999·The Journal of Clinical Investigation·R MahadevaD A Lomas
Aug 23, 2000·Respiratory Medicine·J H Lee, M Brantly
Mar 4, 2011·Respiratory Medicine·Sabina M JanciauskieneTobias Welte
Nov 5, 2013·Archivos de bronconeumología·Beatriz LaraMarc Miravitlles
Jun 28, 2017·International Journal of Chronic Obstructive Pulmonary Disease·Ignacio BlancoMarc Miravitlles
Dec 13, 2017·American Journal of Respiratory Cell and Molecular Biology·Nerea MatamalaBeatriz Martinez-Delgado
Sep 19, 2018·Orphanet Journal of Rare Diseases·Céline RenouxPhilippe Joly
Dec 24, 2018·Clinical Biochemistry·M D SpeevakK R Chapman

❮ Previous
Next ❯

Citations

Jul 28, 2020·American Journal of Respiratory Cell and Molecular Biology·Kenneth R Chapman
Apr 2, 2021·The Application of Clinical Genetics·Susana Seixas, Patricia Isabel Marques
Apr 16, 2021·American Journal of Respiratory and Critical Care Medicine·Andy I RitchieGavin C Donaldson

❮ Previous
Next ❯

Methods Mentioned

BETA
genotyping
PCR
amplicon sequencing
transfection
electrophoresis

Software Mentioned

Polyphen
Ensembl Variant Effect Predictor
CADD
SIFT
Condel

Related Concepts

Related Feeds

American Thoracic Association Journals

Discover the latest respiratory research published by the journals from the American Thoracic Society.