A New SERPINA-1 Missense Mutation Associated with Alpha-1 Antitrypsin Deficiency and Bronchiectasis

Alpha-1-antitrypsin deficiency (AATd) is a hereditary disease, mainly characterized by early onset and the lower lobes’ predominant emphysema. Bronchiectasis is characterized by dilatation of the bronchial wall and a clinical syndrome whose features are a cough, sputum production and frequent respiratory exacerbations. In the literature, there are many papers concerning these two clinical entities, but there is still a lot of debate about a possible association between them, in particular about the frequency of their association and causal links. The aim of this short communication is to show the literature reports about the association between AATd and bronchiectasis to establish the state of the art and possible future developments in this research field.

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“…AAT level was 78 mg/dL. The gene sequencing showed the presence of a novel missense mutation in a heterozygous state on a M3 allele [23].…”

Section: Resultsmentioning

confidence: 94%

Alpha-1-Antitrypsin Deficiency and Bronchiectasis: A Concomitance or a Real Association?

Sanduzzi

Ciasullo²,

Capitelli³

et al. 2020

IJERPH

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“…The question arises here about whether the presence of AAT mutations in these populations is simply an epidemiological coincidence, as part of the wider distribution of some of these genotypes in the population [28,29] or if it has a pathogenetic effect [30,31]. Interestingly, in the case of bronchiectasis, the existence of mutations described in this group seems to point to cases with unique characteristics [32][33][34][35]. Accordingly, some authors suggest screening for AATD in adult patients with non-fully reversible asthma [36].…”

Section: Discussionmentioning

confidence: 99%

Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis

et al. 2022

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Introduction Currently, strategies for improving alpha1 antitrypsin deficiency (AATD) diagnosis are needed. Here we report the performance of a multinational multiplex-based genotyping test on dried blood spots and buccal swabs sent by post or courier and with web registration for subjects with suspected AATD in Argentina, Brazil, Chile, Colombia, Spain, and Turkey. Methods This was an observational, cross-sectional analysis of samples from patients with suspected AATD from March 2018 to January 2022. Samples were coded on a web platform and sent by post or courier to the central laboratory in Northern Spain. Allele-specific genotyping for the 14 most common mutations was carried out with the A1AT Genotyping Test (Progenika-Grifols, Spain). SERPINA1 gene sequencing was performed if none of the mutations were found or one variant was detected in heterozygous status and the AAT serum level was < 60 mg/dl, or if requested by the clinician in charge. Results The study included 30,827 samples: 30,458 (94.7%) with final results after direct genotyping and 369 (1.1%) with additional gene sequencing. Only 0.3% of the samples were not processed due to their poor quality. The prevalence of the most frequent allele combinations was MS 14.7%, MZ 8.6%, SS 1.9%, SZ 1.9%, and ZZ 0.9%. Additionally, 70 cases with new mutations were identified. Family screening was conducted in 2.5% of the samples. Samples from patients with respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations. Conclusions Our results confirm the viability of this diagnostic system for genotyping AATD conducted simultaneously in different countries. The system has proved satisfactory and can improve the timely diagnosis of AATD.

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“…This is important with respect to the development of personalized medicine approaches, as it has been well described that the patient genetic background plays an important role in many liver diseases (e.g. alpha-1 antitrypsin deficiency, hemochromatosis, Wilson’s disease and response to HCV treatment; [46] and reviewed in [7, 47, 48]. The reprogramming efficiency observed for C101 and C496 PLCs was comparable with the efficiency observed for the reprogramming of other cell types (e.g.…”

Section: Discussionmentioning

confidence: 99%

Liver biopsy derived induced pluripotent stem cells provide unlimited supply for the generation of hepatocyte-like cells

et al. 2019

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Background & aims Hepatocyte-like cells (HLCs) differentiated from induced pluripotent stem cells (iPSCs) have emerged as a promising cell culture model to study metabolism, biotransformation, viral infections and inherited liver diseases. iPSCs provide an unlimited supply for the generation of HLCs, but incomplete HLC differentiation remains a major challenge. iPSC may carry-on a tissue of origin dependent expression memory influencing iPSC differentiation into different cell types. Whether liver derived iPSCs (Li-iPSCs) would allow the generation of more fully differentiated HLCs is not known. Methods In the current study, we used primary liver cells (PLCs) expanded from liver needle biopsies and reprogrammed them into Li-iPSCs using a non-integrative Sendai virus-based system. Li-iPSCs were differentiated into HLCs using established differentiation protocols. The HLC phenotype was characterized at the protein, functional and transcriptional level. RNA sequencing data were generated from the originating liver biopsies, the Li-iPSCs, fibroblast derived iPSCs, and differentiated HLCs, and used to characterize and compare their transcriptome profiles. Results Li-iPSCs indeed retain a liver specific transcriptional footprint. Li-iPSCs can be propagated to provide an unlimited supply of cells for differentiation into Li-HLCs. Similar to HLCs derived from fibroblasts, Li-HLCs could not be fully differentiated into hepatocytes. Relative to the originating liver, Li-HLCs showed lower expression of liver specific transcription factors and increased expression of genes involved in the differentiation of other tissues. Conclusions PLCs and Li-iPSCs obtained from small pieces of human needle liver biopsies constitute a novel unlimited source for the production of HLCs. Despite the preservation of a liver specific gene expression footprint in Li-iPSCs, the generation of fully differentiated hepatocytes cannot be achieved with the current differentiation protocols.

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A New SERPINA-1 Missense Mutation Associated with Alpha-1 Antitrypsin Deficiency and Bronchiectasis

Cited by 10 publications

References 17 publications

Alpha-1-Antitrypsin Deficiency and Bronchiectasis: A Concomitance or a Real Association?

Alpha-1-Antitrypsin Deficiency and Bronchiectasis: A Concomitance or a Real Association?

Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis

Liver biopsy derived induced pluripotent stem cells provide unlimited supply for the generation of hepatocyte-like cells

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