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Biomolecules
Special Issues
Rare Diseases Associated with SNPs and Protein Structure Modifications
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Rare Diseases Associated with SNPs and Protein Structure Modifications

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 10340

Special Issue Editors

Prof. Dr. Sabina Janciauskiene

E-Mail Website
Guest Editor
German Center for Lung Research, Hannover, Germany
Interests: alpha1-antitrypsin (AAT); acute inflammation; chronic inflammation; pulmonary disease; cancer; diabetes; inflammatory bowel diseases; skin diseases; liver diseases
Dr. Artur Góra

E-Mail Website1 Website2
Guest Editor
Tunneling Grup, Biotechnology Centre, Silesian University of Technology, Krzywoustego 8, 44-100 Gliwice, Poland
Interests: personalized medicine; molecular modelling; bioinformatics; drug design; protein design and evolution

Special Issue Information

Dear Colleagues,

The early diagnosis and adequate treatment of rare diseases are of great importance. However, due to insufficient data, our knowledge in these aspects is very limited. Genetic disorders often manifest in mutated proteins with modified structure and functionality, and finally lead to changes in metabolic pathways and organism homeostasis. The discovery of the linkage between single-nucleotide modification and the observed dysfunction of the organism is a challenging task, and requires the co-operation of genetics, biochemists, structural biologists, and many other specialists.

The aim of the current Special Issue is to provide substantial contributions to the field examining the structure–function relationship of the changes in proteins caused by single-nucleotide polymorphisms or their combination. We welcome  original research papers presenting novel computational/experimental studies, as well as reviews, in themes including, but not limited to:

  • Newly identified disorders modifying proteins’ function;
  • Studies of the linkages of mutations in proteins with metabolic pathways;
  • Structural analysis of the molecular basis of protein disfunction.

Prof. Dr. Sabina Wallmark
Dr. Artur Góra
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Rare diseases
  • Structure–function relationship
  • SNP
  • Post-translational protein modifications

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Published Papers (3 papers)

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Research

18 pages, 9214 KiB  
Article
Functional and Structural Impact of Deleterious Missense Single Nucleotide Polymorphisms in the NR3C1, CYP3A5, and TNF-α Genes: An In Silico Analysis
by Navakanth Raju Ramayanam, Ranjani Manickam, Vijayakumar Thangavel Mahalingam, Khang Wen Goh, Chrismawan Ardianto, Poovi Ganesan, Long Chiau Ming and Rajanandh Muhasaparur Ganesan
Biomolecules 2022, 12(9), 1307; https://doi.org/10.3390/biom12091307 - 16 Sep 2022
Cited by 5 | Viewed by 2804
Abstract
Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 [...] Read more.
Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 (CYP3A5) play a key role in glucocorticoid resistance susceptibility in humans. Possible causative mutations could be used as therapeutic targets and diagnostic markers for glucocorticoid resistance. This study evaluated the missense SNPs of TNF-α, NR3C1, and CYP3A5 to predict their impact on amino acid changes, protein interaction, and functional stability. The protein sequence of dbSNP was obtained and used online in silico method to screen deleterious mutants for the in silico analysis. In the coding regions of TNF-α, NR3C1, and CYP3A5, 14 deleterious mutations were discovered. The protein functional and stability changes in the amino acid between native and mutant energy were identified by analyzing the changes in the hydrogen bonding of these mutants from native, which were all measured using Swiss PDB and PyMOL. F446S and R439K had the highest root-mean-square deviation (RMSD) values among the 14 deleterious mutants. Additionally, the conserved region of amino acid protein interaction was analyzed. This study could aid in the discovery of new detrimental mutations in TNF-α, NR3C1, and CYP3A5, as well as the development of long-term therapy for corticosteroid resistance in several inflammatory diseases. However, more research into the deleterious mutations of the TNF-α, NR3C1, and CYP3A5 genes is needed to determine their role in corticosteroid resistance. Full article
(This article belongs to the Special Issue Rare Diseases Associated with SNPs and Protein Structure Modifications)
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21 pages, 3347 KiB  
Article
Structural Analysis of the Effect of Asn107Ser Mutation on Alg13 Activity and Alg13-Alg14 Complex Formation and Expanding the Phenotypic Variability of ALG13-CDG
by Karolina Mitusińska, Artur Góra, Anna Bogdańska, Agnieszka Rożdżyńska-Świątkowska, Anna Tylki-Szymańska and Aleksandra Jezela-Stanek
Biomolecules 2022, 12(3), 398; https://doi.org/10.3390/biom12030398 - 4 Mar 2022
Cited by 2 | Viewed by 2528
Abstract
Congenital Disorders of Glycosylation (CDG) are multisystemic metabolic disorders showing highly heterogeneous clinical presentation, molecular etiology, and laboratory results. Here, we present different transferrin isoform patterns (obtained by isoelectric focusing) from three female patients harboring the ALG13 c.320A>G mutation. Contrary to other known [...] Read more.
Congenital Disorders of Glycosylation (CDG) are multisystemic metabolic disorders showing highly heterogeneous clinical presentation, molecular etiology, and laboratory results. Here, we present different transferrin isoform patterns (obtained by isoelectric focusing) from three female patients harboring the ALG13 c.320A>G mutation. Contrary to other known variants of type I CDGs, where transferrin isoelectric focusing revealed notably increased asialo- and disialotransferrin fractions, a normal glycosylation pattern was observed in the probands. To verify this data and give novel insight into this variant, we modeled the human Alg13 protein and analyzed the dynamics of the apo structure and the complex with the UDP-GlcNAc substrate. We also modeled the Alg13-Alg14 heterodimer and ran multiple simulations of the complex in the presence of the substrate. Finally, we proposed a plausible complex formation mechanism. Full article
(This article belongs to the Special Issue Rare Diseases Associated with SNPs and Protein Structure Modifications)
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11 pages, 1594 KiB  
Article
The Relationship between Plasma Alpha-1-Antitrypsin Polymers and Lung or Liver Function in ZZ Alpha-1-Antitrypsin-Deficient Patients
by Annelot D. Sark, Malin Fromme, Beata Olejnicka, Tobias Welte, Pavel Strnad, Sabina Janciauskiene and Jan Stolk
Biomolecules 2022, 12(3), 380; https://doi.org/10.3390/biom12030380 - 28 Feb 2022
Cited by 11 | Viewed by 3486
Abstract
Alpha-1-Antitrypsin (AAT) is a protein of the SERPINA1 gene. A single amino acid mutation (Lys342Glu) results in an expression of misfolded Z-AAT protein, which has a high propensity to intra- and extra-cellular polymerization. Here, we asked whether levels of circulating Z-AAT polymers are [...] Read more.
Alpha-1-Antitrypsin (AAT) is a protein of the SERPINA1 gene. A single amino acid mutation (Lys342Glu) results in an expression of misfolded Z-AAT protein, which has a high propensity to intra- and extra-cellular polymerization. Here, we asked whether levels of circulating Z-AAT polymers are associated with the severity of lung disease, liver disease, or both. We obtained cross sectional data from the Dutch part of the Alpha1 International Registry of 52 ZZ-AAT patients who performed a pulmonary function test and donated a blood sample on the same day. From the Alpha-1 Liver Aachen Registry, we obtained a cohort of 40 ZZ-AAT patients with available data on their liver function. The levels of plasma Z-AAT polymers were determined using a LG96 monoclonal antibody-based sandwich ELISA. In a Dutch cohort, the median plasma level of Z-AAT polymers of patients diagnosed for pulmonary disease was 947.5 µg/mL (733.6–1218 µg/mL (95% CI)), which did not correlate with airflow obstruction or gas transfer value. In the Alpha-1 liver patient cohort, the median polymer level was 1245.9 µg/mL (753–2034 µg/mL (95% CI)), which correlated with plasma gamma-glutamyl transferase (GGT, rs = 0.57, p = 0.001), glutamate dehydrogenase (GLDH, rs = 0.48, p = 0.002) and triglycerides (TG, rs = 0.48, p = 0.0046). A Wilcoxon rank test showed higher Z-AAT polymer values for the liver over the lung group (p < 0.0001). These correlations support a possible link between plasma Z-AAT polymers and the liver function. Full article
(This article belongs to the Special Issue Rare Diseases Associated with SNPs and Protein Structure Modifications)
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