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Description of 22 new alpha-1 antitrypsin genetic variants.

ABSTRACT: 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.

SUBMITTER: Renoux C

PROVIDER: S-EPMC6142351 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Description of 22 new alpha-1 antitrypsin genetic variants.

Renoux Céline C Odou Marie-Françoise MF Tosato Guillaume G Teoli Jordan J Abbou Norman N Lombard Christine C Zerimech Farid F Porchet Nicole N Chapuis Cellier Colette C Balduyck Malika M Joly Philippe P

Orphanet journal of rare diseases 20180917 1

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 ...[more]

PMID: 30223862

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Project description:BackgroundAlpha-1 antitrypsin deficiency (AATD) is characterized by reduced serum levels of the AAT protein and predisposes to liver and lung disease. The characterization at structural level of novel pathogenic SERPINA1 mutants coding for circulating AAT could provide novel insights into the mechanisms of AAT misfolding. The present study aimed to provide a practical framework for the identification and analysis of new AAT mutations, combining structural simulations and clinical data.MethodsWe analysed a total of five mutations (four not previously described) in a total of six subjects presenting moderate to severe AATD: Gly95Alafs*18, Val210Glu, Asn247Ser, Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile. Clinical data, genotyping and phenotyping assays, structural mapping, and conformational characterization through molecular dynamic (MD) simulations were developed and combined.ResultsNewly discovered AAT missense variants were localized both on the interaction surface and the hydrophobic core of the protein. Distribution of mutations across the structure revealed Val210Glu at the solvent exposed s4C strand and close to the "Gate" region. Asn247Ser was located on the accessible surface, which is important for glycan attachment. On the other hand, Asp341His, Leu383Phe were mapped close to the "breach" and "shutter" regions. MD analysis revealed the reshaping of local interactions around the investigated substitutions that have varying effects on AAT conformational flexibility, hydrophobic packing, and electronic surface properties. The most severe structural changes were observed in the double- and triple-mutant (Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile) molecular models. The two carriers presented impaired lung function.ConclusionsThe results characterize five variants, four of them previously unknown, of the SERPINA1 gene, which define new alleles contributing to the deficiency of AAT. Rare variants might be more frequent than expected, and therefore, in discordant cases, standardized screening of the S and Z alleles needs complementation with gene sequencing and structural approaches. The utility of computational modelling for providing supporting evidence of the pathogenicity of rare single nucleotide variations is discussed.

Project description:BackgroundAlpha 1 Antitrypsin Deficiency (AATD) is a largely underrecognized genetic condition characterized by low Alpha 1 Antitrypsin (AAT) serum levels, resulting from variations in SERPINA1. Many individuals affected by AATD are thought to be undiagnosed, leading to poor patient outcomes. The Z (c.1096G > A; p.Glu366Lys) and S (c.863A > T; p.Glu288Val) deficiency variants are the most frequently found variants in AATD, with the Z variant present in most individuals diagnosed with AATD. However, there are many other less frequent variants known to contribute to lung and/or liver disease in AATD. To identify the most common rare variants associated with AATD, we conducted a systematic literature review with the aim of assessing AATD variation patterns across the world.MethodsA systematic literature search was performed to identify published studies reporting AATD/SERPINA1 variants. Study eligibility was assessed for the potential to contain relevant information, with quality assessment and data extraction performed on studies meeting all eligibility criteria. AATD variants were grouped by variant type and linked to the geographical region identified from the reporting article.ResultsOf the 4945 articles identified by the search string, 864 contained useful information for this study. Most articles came from the United States, followed by the United Kingdom, Germany, Spain, and Italy. Collectively, the articles identified a total of 7631 rare variants and 216 types of rare variant across 80 counties. The F (c.739C > T; p.Arg247Cys) variant was identified 1,281 times and was the most reported known rare variant worldwide, followed by the I (c.187C > T; p.Arg63Cys) variant. Worldwide, there were 1492 Null/rare variants that were unidentified at the time of source article publication and 75 rare novel variants reported only once.ConclusionAATD goes far beyond the Z and S variants, suggesting there may be widespread underdiagnosis of patients with the condition. Each geographical region has its own distinctive variety of AATD variants and, therefore, comprehensive testing is needed to fully understand the true number and type of variants that exist. Comprehensive testing is also needed to ensure accurate diagnosis, optimize treatment strategies, and improve outcomes for patients with AATD.

Project description:BACKGROUND:Alpha-1-antitrypsin (AAT) deficiency (AATD) of Z, Mmalton, Siiyama type is associated with liver storage of the mutant proteins and liver disease. The Z variant can be diagnosed on isoelectric focusing (IEF) while Mmalton and Siiyama may be missed or misdiagnosed with this technique. Therefore, molecular analysis is mandatory for their characterization. In particular, that holds true for the Mmalton variant as on IEF profile it resembles the wild M2 subtype. METHODS:This is a retrospective analysis involving review of medical records and of liver biopsy specimens from a series of Mmalton, Z and Siiyama Alpha-1-antitrypsin deficiency patients. The review has been implemented by additional histological stains, electron microscopic observations and 3-D modeling studies of the sites of the mutations. RESULTS:Z, Mmalton and Siiyama liver specimen contained characteristic intrahepatocytic PAS-D globules. The globules differed in the three variants as only Mmalton cases showed dark basophilic precipitates within the AAT inclusions. The precipitates were visualized in haematoxylin-eosin (H.E.) stained preparations and corresponded to calcium precipitates as demonstrated by von Kossa staining. On immunohistochemistry, ZAAT inclusions were stained by polyclonal as well as monoclonal noncommercial anti-AAT antibody (AZT11), whilst Mmalton and Siiyama inclusion bodies remained negative with the monoclonal anti-Z antibody. 3-D protein analysis allowed to predict more severe misfolding of the Mmalton molecule as compared to Z and Siiyama that could trigger anomalous interaction with endoplasmic reticulum chaperon proteins, namely calcium binding proteins. CONCLUSIONS:Mmalton AAT inclusion bodies contain calcium precipitates inside them that allow the differential diagnosis with Siiyama and ZAAT inclusions in routine histological sections. The study has confirmed the specificity of the monoclonal AZT11 for the Z mutant. Thus, the combination of these two features is crucial for the distinction between the three variants and for predicting the genotype, whose confirmation would definitely require molecular analysis. Our study provides new data on the pathomorphogenesis of Mmalton inclusion bodies whose mineralization could play a central role in disease pathogenesis of Mmalton that is distinct from the Z and Siiyama variants. Calcium is known to be a major effector of cell death either via the increased intracellular concentration or the alteration of homeostasis.

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Description of 22 new alpha-1 antitrypsin genetic variants.

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Description of 22 new alpha-1 antitrypsin genetic variants.

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