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Proteins and Mutations: Inherited Diseases, Drug Resistance and Pharmacogenomics
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Proteins and Mutations: Inherited Diseases, Drug Resistance and Pharmacogenomics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 3953

Special Issue Editors

Prof. Dr. Ozlem Tastan Bishop

E-Mail Website
Guest Editor
Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6139, South Africa
Interests: structural bioinformatics and its applications to drug discovery
Prof. Dr. Carlo R. Largiadèr

E-Mail Website
Guest Editor
Pharmacogenomics and Drug Metabolism Research Group, Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
Interests: study of genomic variation as predictive or prognostic markers in the context of drug therapies

Special Issue Information

Dear Colleagues,

Genetic variations that result in changes in amino acids can have striking effects on proteins. These effects can lead to inherited diseases; cause drug resistance in both communicable and non-communicable diseases; and play an important role in pathogenicity and infectivity, among many other biological phenomena. Hence, deciphering the impact of mutations, particularly missense mutations, on protein structure and function would help to understand their effects, which would ultimately guide the design of safer and more effective therapies or the safer use of current treatments. In this context, this Special Issue aims to cover different aspects of mutations and their structural as well as functional effects on proteins, and welcomes contributions from, but not limited to, biochemical, computational, and structural studies in the form of original research articles or up-to-date reviews.

Prof. Dr. Ozlem Tastan Bishop
Prof. Dr. Carlo R. Largiadèr
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • allostery
  • cancer
  • drug metabolism
  • drug resistance
  • drug and vaccine development
  • infectious diseases
  • missense mutations
  • pathogenicity
  • pharmacogenomics
  • rare diseases

Published Papers (4 papers)

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Research

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15 pages, 1155 KiB  
Article
Approach for Phased Sequence-Based Genotyping of the Critical Pharmacogene Dihydropyrimidine Dehydrogenase (DPYD)
by Alisa Ambrodji, Angélique Sadlon, Ursula Amstutz, Dennis Hoch, Martin D. Berger, Sara Bastian, Steven M. Offer and Carlo R. Largiadèr
Int. J. Mol. Sci. 2024, 25(14), 7599; https://doi.org/10.3390/ijms25147599 - 11 Jul 2024
Viewed by 272
Abstract
Pre-treatment genotyping of four well-characterized toxicity risk-variants in the dihydropyrimidine dehydrogenase gene (DPYD) has been widely implemented in Europe to prevent serious adverse effects in cancer patients treated with fluoropyrimidines. Current genotyping practices are largely limited to selected commonly studied variants [...] Read more.
Pre-treatment genotyping of four well-characterized toxicity risk-variants in the dihydropyrimidine dehydrogenase gene (DPYD) has been widely implemented in Europe to prevent serious adverse effects in cancer patients treated with fluoropyrimidines. Current genotyping practices are largely limited to selected commonly studied variants and are unable to determine phasing when more than one variant allele is detected. Recent evidence indicates that common DPYD variants modulate the functional impact of deleterious variants in a phase-dependent manner, where a cis- or a trans-configuration translates into different toxicity risks and dosing recommendations. DPYD is a large gene with 23 exons spanning nearly a mega-base of DNA, making it a challenging candidate for full-gene sequencing in the diagnostic setting. Herein, we present a time- and cost-efficient long-read sequencing approach for capturing the complete coding region of DPYD. We demonstrate that this method can reliably produce phased genotypes, overcoming a major limitation with current methods. This method was validated using 21 subjects, including two cancer patients, each of whom carried multiple DPYD variants. Genotype assignments showed complete concordance with conventional approaches. Furthermore, we demonstrate that the method is robust to technical challenges inherent in long-range sequencing of PCR products, including reference alignment bias and PCR chimerism. Full article
(This article belongs to the Special Issue Proteins and Mutations: Inherited Diseases, Drug Resistance and Pharmacogenomics)
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13 pages, 535 KiB  
Article
The Importance of the FUT2 rs602662 Polymorphism in the Risk of Cardiovascular Complications in Patients after Kidney Transplantation
by Maciej Józef Kotowski, Piotr Ostrowski, Jerzy Sieńko, Bogusław Czerny, Karol Tejchman, Bogusław Machaliński, Aleksandra Górska, Aleksandra E. Mrozikiewicz and Anna Bogacz
Int. J. Mol. Sci. 2024, 25(12), 6562; https://doi.org/10.3390/ijms25126562 - 14 Jun 2024
Viewed by 454
Abstract
The FUT2 gene encodes an enzyme called α-1,2-fucosyltransferase, which is involved in the formation of blood group antigens AB0(H) and is also involved in the processes of vitamin B12 absorption and its transport between cells. FUT2 gene polymorphisms are associated with vitamin B12 [...] Read more.
The FUT2 gene encodes an enzyme called α-1,2-fucosyltransferase, which is involved in the formation of blood group antigens AB0(H) and is also involved in the processes of vitamin B12 absorption and its transport between cells. FUT2 gene polymorphisms are associated with vitamin B12 levels in the body. Vitamin B12 deficiency associated with hyperhomocysteinemia is a major risk factor for cardiovascular diseases (CVDs), which are one of the main causes of death in patients after kidney transplantation. The aim of our study was to determine the impact of the rs602662 (G>A) polymorphism of the FUT2 gene on the functionality of transplanted kidneys and the risk of CVD in patients after kidney transplantation. The study included 402 patients treated with immunosuppression (183 patients taking cyclosporine (CsA) and 219 patients taking tacrolimus (TAC)). The analysis of the FUT2 rs602662 (G>A) polymorphism was performed using real-time PCR. Patients with CsA were more likely to be underweight (1.64% vs. 0.91%) and obese (27.87% vs. 15.98%), while those taking TAC were more likely to be of normal weight (39.27%) or overweight (43.84%). No statistically significant differences were observed comparing the mean blood pressure, both systolic and diastolic. The renal profile showed a higher median urea nitrogen concentration in patients with CsA (26.45 mg/dL (20.60–35.40) vs. 22.95 mg/dL (17.60–33.30), p = 0.004). The observed frequency of rs602662 alleles of the FUT2 gene was similar in the analyzed groups. The A allele was present in 43.7% of patients with CsA and 41.1% of those taking TAC (OR = 0.898; 95% CI: 0.678–1.189; p = 0.453). In the group with CsA, the GG genotype was present in 32.2% of patients, the GA in 48.1% and the AA in 19.7%. A similar distribution was obtained in the TAC group: GG—33.8%, GA—50.2%, and AA—16.0%. An association of genotypes containing the G allele with a higher incidence of hypertension was observed. The G allele was present in 65% of people with hypertension and in 56% of patients with normal blood pressure (p = 0.036). Moreover, the evaluation of the renal parameters showed no effect of the FUT2 polymorphism on the risk of organ rejection because the levels of creatinine, eGFR, potassium, and urea nitrogen were prognostic of successful transplantation. Our results suggest that the rs6022662 FUT2 polymorphism may influence the risk of cardiovascular diseases. Full article
(This article belongs to the Special Issue Proteins and Mutations: Inherited Diseases, Drug Resistance and Pharmacogenomics)
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21 pages, 3369 KiB  
Article
An Activated Dendritic-Cell-Related Gene Signature Indicative of Disease Prognosis and Chemotherapy and Immunotherapy Response in Colon Cancer Patients
by Yiben Ouyang, Mingqian Yu, Tiange Liu, Mengying Suo, Jingyi Qiao, Liqiang Wang and Na Li
Int. J. Mol. Sci. 2023, 24(21), 15959; https://doi.org/10.3390/ijms242115959 - 3 Nov 2023
Cited by 1 | Viewed by 1267
Abstract
Accumulating evidence has underscored the prognostic value of tumor-infiltrating immune cells in the tumor microenvironment of colon cancer (CC). In this retrospective study, based on publicly available transcriptome profiles and clinical data from the Gene Expression Omnibus and The Cancer Genome Atlas databases, [...] Read more.
Accumulating evidence has underscored the prognostic value of tumor-infiltrating immune cells in the tumor microenvironment of colon cancer (CC). In this retrospective study, based on publicly available transcriptome profiles and clinical data from the Gene Expression Omnibus and The Cancer Genome Atlas databases, we derived and verified an activated dendritic cell (aDC)-related gene signature (aDCRS) for predicting the survival outcomes and chemotherapy and immunotherapy response of CC patients. We quantified the infiltration abundance of 22 immune cell subtypes via the “CIBERSORT” R script. Univariate Cox proportional hazards (PHs) regression was used to identify aDC as the most robust protective cell type for CC prognosis. After selecting differentially expressed genes (DEGs) significantly correlated with aDC infiltration, we performed univariate Cox-PH regression, LASSO regression, and stepwise multivariate Cox-PH regression successively to screen out prognosis-related genes from selected DEGs for constructing the aDCRS. Receiver operating characteristic (ROC) curves and Kaplan–Meier (KM) analysis were employed to assess the discriminatory ability and risk-stratification capacity. The “oncoPredict” package, Cancer Treatment Response gene signature DataBase, and Tumor Immune Dysfunction and Exclusion algorithm were utilized to estimate the practicability of the aDCRS in predicting response to chemotherapy and immune checkpoint blockade. Gene set enrichment analysis and single-cell RNA sequencing analysis were also implemented. Furthermore, an aDCRS-based nomogram was constructed and validated via ROC curves, calibration plots and decision curve analysis. In conclusion, aDCRS and an aDCRS-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions, thus improving the survival outcomes of CC patients in the future. Full article
(This article belongs to the Special Issue Proteins and Mutations: Inherited Diseases, Drug Resistance and Pharmacogenomics)
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Review

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15 pages, 1937 KiB  
Review
Challenges of Diagnosing Mendelian Susceptibility to Mycobacterial Diseases in South Africa
by Denise Scholtz, Tracey Jooste, Marlo Möller, Ansia van Coller, Craig Kinnear and Brigitte Glanzmann
Int. J. Mol. Sci. 2023, 24(15), 12119; https://doi.org/10.3390/ijms241512119 - 28 Jul 2023
Cited by 2 | Viewed by 1475
Abstract
Inborn errors of immunity (IEI) are genetic disorders with extensive clinical presentations. They can range from increased susceptibility to infections to significant immune dysregulation that results in immune impairment. While IEI cases are individually rare, they collectively represent a significant burden of disease, [...] Read more.
Inborn errors of immunity (IEI) are genetic disorders with extensive clinical presentations. They can range from increased susceptibility to infections to significant immune dysregulation that results in immune impairment. While IEI cases are individually rare, they collectively represent a significant burden of disease, especially in developing countries such as South Africa, where infectious diseases like tuberculosis (TB) are endemic. This is particularly alarming considering that certain high penetrance mutations that cause IEI, such as Mendelian Susceptibility to Mycobacterial Disease (MSMD), put individuals at higher risk for developing TB and other mycobacterial diseases. MSMD patients in South Africa often present with different clinical phenotypes than those from the developed world, therefore complicating the identification of disease-associated variants in this setting with a high burden of infectious diseases. The lack of available data, limited resources, as well as variability in clinical phenotype are the reasons many MSMD cases remain undetected or misdiagnosed. This article highlights the challenges in diagnosing MSMD in South Africa and proposes the use of transcriptomic analysis as a means of potentially identifying dysregulated pathways in affected African populations. Full article
(This article belongs to the Special Issue Proteins and Mutations: Inherited Diseases, Drug Resistance and Pharmacogenomics)
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