Characterization of Novel Missense Variants of <i>SERPINA1</i> Gene Causing Alpha-1 Antitrypsin Deficiency

Matamala, Nerea; Lara, Beatríz; Gómez-Mariano, Gema; Martínez, Samuel Jesús; Retana, Diana; Fernandez, T; Silvestre, Ramona A.; Belmonte, Irene; Rodríguez‐Frías, Francisco; Vilar, Marçal; Sáez, Raquel; Iturbe, Igor; Castillo, Silvia; Molina-Molina, María; Texidó, Anna; Tirado-Conde, Gema; Lόpez-Campos, José Luís; Posada, Manuel; Blanco, Ignacio; Janciauskiene, Sabina; Martı́nez-Delgado, Beatriz

doi:10.1165/rcmb.2017-0179oc

Cited by 24 publications

(22 citation statements)

References 48 publications

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“…When cultured in vitro, these cells undergo dedifferentiation, causing them to lose hepatocyte function. To solve the above issues, the development of new models allowing the culture and study of functional human hepatocytes is of great need [19][20][21].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, in this study we established human liver organoid cultures reproducing the main characteristics of the wild-type M and pathogenic, deficient ZZ and MZ variants of AAT protein. When compared to 2D cell models [19], organoids are closer to liver tissue with respect to morphology, gene expression, and protein secretion. For example, the liver produces and secretes major proteins into the circulation, such as albumin, AAT, fibrinogens and apolipoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…Since organoids are derived directly from the affected individuals, they may also help us to elucidate the complex heterogeneity of liver disease among AATD carriers. In addition to Z-AAT mutation, many other rare alleles associated with AAT deficiency have been described [19,28,29] for which the potential damaging effects in hepatocytes are unknown. Organoids derived from patients carrying other than the Z variant would help to investigate the mechanisms of accumulation, secretion and degradation of these much less studied AAT variants.…”

Section: Discussionmentioning

confidence: 99%

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Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

et al. 2019

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Background and aims Alpha-1 antitrypsin (AAT) is a product of SERPINA1 gene mainly expressed by hepatocytes. Clinically relevant mutations in the SERPINA1 gene, such as Z (Glu342Lys), results in an expression of misfolded AAT protein having high propensity to polymerize, accumulate in hepatocytes and thus to enhance a risk for hepatocyte damage and subsequent liver disease. So far, the relationship between the Z-AAT accumulation and liver cell damage remains not completely understood. We present three-dimensional organoid culture systems, as a novel tool for modeling Z-AAT-related liver diseases. Methods We have established liver organoids from liver biopsies of patients with homozygous (ZZ) and heterozygous (MZ) deficiency and normal (MM) genotypes of AAT. The features of these organoid models were characterized by analyzing AAT protein secretion and intracellular aggregation in MZ and ZZ genotypes as well as SERPINA1 expression in differentiated cultures. Results Transcriptional analysis of differentiated organoid cultures by RNA-Seq showed hepatocyte-specific gene expression profile. Genes, such as ALB, APOB, CYP3A4 and SERPINA1, were validated and confirmed through quantitative-PCR analysis. The organoids from MZ and ZZ cases showed intracellular aggregation and lower secretion of AAT protein, and lower expression of ALB and APOB, as typically seen in hepatocytes from Z-AAT deficiency patients. Furthermore, organoids responded to external stimulus. Treatment with oncostatin M, a well-known inducer of SERPINA1, increased expression of the full-length transcripts (AAT-1C) as well as the short transcript of AAT (AAT-ST1C4). Conclusions Liver organoid model recapitulates the key features of Z-AAT deficiency and provides a useful tool for disease modeling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

et al. 2019

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“…Very interestingly, we also identified during the course of this study two SERPINA1 deficient variants that were very recently described: Trento (p.Glu99Val) [ 14 ] and S Donosti (p.Ser38Phe) [ 15 ]. The Trento variant showed compromised conformational stability after secretion from the hepatocyte [ 14 ].…”

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confidence: 65%

Description of 22 new alpha-1 antitrypsin genetic variants

Renoux

Odou

Tosato

et al. 2018

Orphanet J Rare Dis

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Alpha-1 antitrypsin deficiency is an autosomal co-dominant disorder caused by mutations of the highly polymorphic SERPINA1 gene. This genetic disorder still remains largely under-recognized and can be associated with lung and/or liver injury. The laboratory testing for this deficiency typically comprises serum alpha-1 antitrypsin quantification, phenotyping according to the isoelectric focusing pattern and genotyping if necessary. To date, more than 100 SERPINA1 variants have been described and new genetic variants are frequently discovered. Over the past 10 years, 22 new genetic variants of the SERPINA1 gene were identified in the daily practice of the University Medical laboratories of Lille and Lyon (France). Among these 22 variants, seven were Null alleles and one with a M1 migration pattern (M1Cremeaux) was considered as deficient according to the clinical and biological data and to the American College of Medical Genetics and Genomics (ACMG) criteria. Three other variants were classified as likely pathogenic, three as variants of uncertain significance while the remaining ones were assumed to be neutral. Moreover, we also identified in this study two recently described SERPINA1 deficient variants: Trento (p.Glu99Val) and SDonosti (p.Ser38Phe). The current data, together with a recent published meta-analysis, represent the most up-to-date list of SERPINA1 variants available so far.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0897-0) contains supplementary material, which is available to authorized users.

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“…In this context, the potential role of evaluating anti-elastase activity could be of help. Anti-elastase activity is one of the main markers in the importance of a specific mutation [66]. Beyond serum AAT levels, anti-elastase activity is also influenced by external and environmental factors like alcohol intake [67] or active smoking [68], as well as by inorganic compounds [69] and inflammatory processes [70].…”

Section: The Future: a Second Change Of Paradigm Comingmentioning

confidence: 99%

Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy

Lόpez-Campos

Hernández

Eraso

2020

JCM

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Ever since the first studies, restoring proteinase imbalance in the lung has traditionally been considered as the main goal of alpha1 antitrypsin (AAT) replacement therapy. This strategy was therefore based on ensuring biochemical efficacy, identifying a protection threshold, and evaluating different dosage regimens. Subsequently, the publication of the results of the main clinical trials showing a decrease in the progression of pulmonary emphysema has led to a debate over a possible change in the main objective of treatment, from biochemical efficacy to clinical efficacy in terms of lung densitometry deterioration prevention. This new paradigm has produced a series controversies and unanswered questions which face clinicians managing AAT deficiency. In this review, the concepts that led to the approval of AAT replacement therapy are reviewed and discussed under a new prism of achieving clinical efficacy, with the reduction of lung deterioration as the main objective. Here, we propose the use of current knowledge and clinical experience to face existing challenges in different clinical scenarios, in order to help clinicians in decision-making, increase interest in the disease, and stimulate research in this field.

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Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency

Cited by 24 publications

References 48 publications

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

Description of 22 new alpha-1 antitrypsin genetic variants

Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy

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