Alpha 1-antitrypsin nonsense mutation associated with a retained truncated protein and reduced mRNA

Molecular Genetics and Metabolism
J LeeM Brantly

Abstract

alpha 1-Antitrypsin (alpha 1AT) provides the major protection in the lung against neutrophil elastase-mediated proteolysis. Inheritance of alpha 1AT deficiency alleles is associated with an increased risk of emphysema and liver disease. alpha 1AT null alleles cause the total absence of serum alpha 1AT and represent the ultimate in a continuum of alleles associated with alpha 1AT deficiency. The molecular mechanisms responsible for absence of serum alpha 1AT include splicing abnormalities, deletion of alpha 1AT coding exons, and premature stop codons. We identified an Italian individual with asthma, emphysema, and a very low level of serum alpha 1AT. DNA sequencing demonstrated the Mprocida deficiency allele and a novel null allele, QOtrastevere (c654 G-->A, W194Z), a nonsense mutation near the intron 2 (IVS2) splice acceptor site. To determine the molecular basis of QOtrastevere and specifically to evaluate whether this nonsense mutation interfered with mRNA processing by altered splicing, we used a Chinese hamster ovary cell line permanently transfected with QOtrastevere or normal M alpha 1AT with and without IVS2. Northern blot analysis demonstrated that the normal M construct, with or without IVS2, expressed alpha 1AT mRNA o...Continue Reading

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Citations

Jan 21, 2011·European Journal of Human Genetics : EJHG·Sabina JanciauskieneMaurizio Luisetti
Jul 21, 2001·Molecular and Cellular Biology·K S Rajavel, E F Neufeld
Nov 27, 2014·Orphanet Journal of Rare Diseases·Ilaria FerrarottiMaurizio Luisetti
Oct 8, 2014·Respiratory Research·Beatriz LaraBeatriz Martínez-Delgado
Jul 5, 2015·Journal of Translational Medicine·Nerea MatamalaBeatriz Martinez-Delgado
Feb 24, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Emer P ReevesNoel G McElvaney
Aug 23, 2000·Respiratory Medicine·J H Lee, M Brantly

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