ArticleRespiratory research2014
Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid.
Article in Respiratory research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- Rare variants in alpha 1 antitrypsin deficiency: a systematic literature review.Orphanet journal of rare diseases · 2024Pooled it
- αThe journal of allergy and clinical immunology. In practice · 2025Article
- Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network.Human genomics · 2023Article
- Novel SERPINA1 Alleles Identified through a Large Alpha-1 Antitrypsin Deficiency Screening Program and Review of Known Variants.Chronic obstructive pulmonary diseases (Miami, Fla.) · 2023Article
- Clinical characterization of a novel alpha1-antitrypsin null variant: PiQ0Respiratory medicine case reports · 2022Article
- Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview ofThe application of clinical genetics · 2021Review
- Comprehensive Functional Characterization and Clinical Interpretation of 20 Splice-Site Variants of theCancers · 2020Article
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- Minigene Splicing Assays Identify 12 Spliceogenic Variants ofFrontiers in genetics · 2019Article
- Identification of Eight Spliceogenic Variants in BRCA2 Exon 16 by Minigene Assays.Frontiers in genetics · 2018Article
- Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18.PLoS genetics · 2017Article
- Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis.Therapeutic advances in respiratory disease · 2016Review
- Clinical heterogeneity and potential high pathogenicity of the Mmalton Alpha 1 antitrypsin allele at the homozygous, compound heterozygous and heterozygous states.Orphanet journal of rare diseases · 2015Article
- Alternative transcripts of the SERPINA1 gene in alpha-1 antitrypsin deficiency.Journal of translational medicine · 2015Article
- Identification of a novel SERPINA-1 mutation causing alpha-1 antitrypsin deficiency in a patient with severe bronchiectasis and pulmonary embolism.International journal of chronic obstructive pulmonary disease · 2015Article
- Identification and characterisation of eight novel SERPINA1 Null mutations.Orphanet journal of rare diseases · 2014Article
- Update on and future perspectives for the diagnosis of alpha-1 antitrypsin deficiency in Brazil.Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e TisilogiaArticle
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Authors and funding
12 authors at 8 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundSevere Alpha-1 Antitrypsin (AAT) deficiency is a hereditary condition caused by mutations in the SERPINA1 gene, which predisposes to lung emphysema and liver disease. It is usually related to PI*Z alleles, and less frequent to rare and null (QO) alleles. Null-AAT alleles represent the end of a continuum of variants associated with profound AAT deficiency and extremely increased risk of emphysema.
methodsA family with severe AAT deficiency was analyzed to achieve genetic diagnosis. The complete exons and introns of the SERPINA1 gene were sequenced and transcriptional analysis by RT-PCR was performed to characterize the effect of splicing variants found in the patients. In addition, a minigene MGserpa1_ex1b-1c was cloned into the pSAD vector to in vitro investigate the independent impact of variants on splicing process.
resultsWe report a new identified null allele (PI*QOMadrid) in two adult siblings with practically no detectable serum AAT. The PI*QOMadrid allele consist of a duplication of the thymine (T) in position +2 of the donor splice site of exon 1C (+2dupT). In these two subjects, PI*QOMadrid occurred in compound heterozygote combination with the previously described variant PI*QOPorto. Both QOMadrid and QOPorto variants are located very close together in a regulatory region of the SERPINA1 gene. Analysis of transcripts revealed that QOMadrid variant prevented the expression of transcripts from exon 1C, and then normally spliced RNA products are not expected in the liver of these patients. In addition, aberrant splicing patterns of both variants were clearly distinguished and quantified by functional in vitro assays lending further support to their pathogenicity.
conclusionFinding pathogenic mutations in non-coding regions of the SERPINA1 highlight the importance that regulatory regions might have in the disease. Regulatory regions should be seriously considered in discordant cases with severe AAT deficiency where no coding mutations were found.
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