Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency
Abstract Background Alpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the ‘Z’ and ‘S’ variants...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | BMC Medical Genetics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12881-019-0852-5 |
| _version_ | 1818611439853633536 |
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| author | Friedrich Kueppers Mark D. Andrake Qifang Xu Roland L. Dunbrack Joannah Kim Christopher L. Sanders |
| author_facet | Friedrich Kueppers Mark D. Andrake Qifang Xu Roland L. Dunbrack Joannah Kim Christopher L. Sanders |
| author_sort | Friedrich Kueppers |
| collection | DOAJ |
| description | Abstract Background Alpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the ‘Z’ and ‘S’ variants – single-nucleotide variations (SNVs) that result in amino acid substitutions of E342K and E264V. However, SERPINA1 is highly polymorphic, with numerous potentially clinically relevant variants reported. Novel variants continue to be discovered, and without reports of pathogenicity, it can be difficult for clinicians to determine the best course of treatment. Methods We assessed the utility of next-generation sequencing (NGS) and predictive computational analysis to guide the diagnosis of patients suspected of having AATD. Blood samples on serum separator cards were submitted to the DNA1 Advanced Screening Program (Biocerna LLC, Fulton, Maryland, USA) by physicians whose patients were suspected of having AATD. Laboratory analyses included quantification of serum AAT levels, qualitative analysis by isoelectric focusing, and targeted genotyping and NGS of the SERPINA1 gene. Molecular modeling software UCSF Chimera (University College of San Francisco, CA) was used to visualize the positions of amino acid changes as a result of rare/novel SNVs. Predictive software was used to assess the potential pathogenicity of these variants; methods included a support vector machine (SVM) program, PolyPhen-2 (Harvard University, Cambridge, MA), and FoldX (Centre for Genomic Regulation, Barcelona, Spain). Results Samples from 23 patients were analyzed; 21 rare/novel sequence variants were identified by NGS, including splice variants (n = 2), base pair deletions (n = 1), stop codon insertions (n = 2), and SNVs (n = 16). Computational modeling of protein structures caused by the novel SNVs showed that 8 were probably deleterious, and two were possibly deleterious. For the majority of probably/possibly deleterious SNVs (I50N, P289S, M385T, M221T, D341V, V210E, P369H, V333M and A142D), the mechanism is probably via disruption of the packed hydrophobic core of AAT. Several deleterious variants occurred in combination with more common deficiency alleles, resulting in very low AAT levels. Conclusions NGS and computational modeling are useful tools that can facilitate earlier, more precise diagnosis, and consideration for AAT therapy in AATD. |
| first_indexed | 2024-12-16T15:30:21Z |
| format | Article |
| id | doaj.art-d32b605cb01a47899ade581892491c43 |
| institution | Directory Open Access Journal |
| issn | 1471-2350 |
| language | English |
| last_indexed | 2024-12-16T15:30:21Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genetics |
| spelling | doaj.art-d32b605cb01a47899ade581892491c432022-12-21T22:26:22ZengBMCBMC Medical Genetics1471-23502019-07-0120111910.1186/s12881-019-0852-5Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin DeficiencyFriedrich Kueppers0Mark D. Andrake1Qifang Xu2Roland L. Dunbrack3Joannah Kim4Christopher L. Sanders5Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple UniversityMolecular Therapeutics Program, Institute for Cancer Research, Fox Chase Cancer CenterMolecular Therapeutics Program, Institute for Cancer Research, Fox Chase Cancer CenterMolecular Therapeutics Program, Institute for Cancer Research, Fox Chase Cancer CenterBiocerna LLCBiocerna LLCAbstract Background Alpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the ‘Z’ and ‘S’ variants – single-nucleotide variations (SNVs) that result in amino acid substitutions of E342K and E264V. However, SERPINA1 is highly polymorphic, with numerous potentially clinically relevant variants reported. Novel variants continue to be discovered, and without reports of pathogenicity, it can be difficult for clinicians to determine the best course of treatment. Methods We assessed the utility of next-generation sequencing (NGS) and predictive computational analysis to guide the diagnosis of patients suspected of having AATD. Blood samples on serum separator cards were submitted to the DNA1 Advanced Screening Program (Biocerna LLC, Fulton, Maryland, USA) by physicians whose patients were suspected of having AATD. Laboratory analyses included quantification of serum AAT levels, qualitative analysis by isoelectric focusing, and targeted genotyping and NGS of the SERPINA1 gene. Molecular modeling software UCSF Chimera (University College of San Francisco, CA) was used to visualize the positions of amino acid changes as a result of rare/novel SNVs. Predictive software was used to assess the potential pathogenicity of these variants; methods included a support vector machine (SVM) program, PolyPhen-2 (Harvard University, Cambridge, MA), and FoldX (Centre for Genomic Regulation, Barcelona, Spain). Results Samples from 23 patients were analyzed; 21 rare/novel sequence variants were identified by NGS, including splice variants (n = 2), base pair deletions (n = 1), stop codon insertions (n = 2), and SNVs (n = 16). Computational modeling of protein structures caused by the novel SNVs showed that 8 were probably deleterious, and two were possibly deleterious. For the majority of probably/possibly deleterious SNVs (I50N, P289S, M385T, M221T, D341V, V210E, P369H, V333M and A142D), the mechanism is probably via disruption of the packed hydrophobic core of AAT. Several deleterious variants occurred in combination with more common deficiency alleles, resulting in very low AAT levels. Conclusions NGS and computational modeling are useful tools that can facilitate earlier, more precise diagnosis, and consideration for AAT therapy in AATD.http://link.springer.com/article/10.1186/s12881-019-0852-5Alpha 1 Antitrypsin DeficiencySERPINA1Rare variantsProtein modeling |
| spellingShingle | Friedrich Kueppers Mark D. Andrake Qifang Xu Roland L. Dunbrack Joannah Kim Christopher L. Sanders Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency BMC Medical Genetics Alpha 1 Antitrypsin Deficiency SERPINA1 Rare variants Protein modeling |
| title | Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency |
| title_full | Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency |
| title_fullStr | Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency |
| title_full_unstemmed | Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency |
| title_short | Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency |
| title_sort | protein modeling to assess the pathogenicity of rare variants of serpina1 in patients suspected of having alpha 1 antitrypsin deficiency |
| topic | Alpha 1 Antitrypsin Deficiency SERPINA1 Rare variants Protein modeling |
| url | http://link.springer.com/article/10.1186/s12881-019-0852-5 |
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