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Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition
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Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition

A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 20 April 2026 | Viewed by 18719

Special Issue Editor

Prof. Dr. Grzegorz Wegrzyn

E-Mail Website
Guest Editor
Department of Molecular Biology, University of Gdańsk, Gdańsk, Poland
Interests: gene expression regulation; DNA replication; bacteriophages; plasmids; human genetic diseases; neurodegeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Complex Molecular Mechanism of Monogenic Diseases 2.0” (https://www.mdpi.com/journal/cimb/special_issues/IL4684WI14).

Monogenic diseases are defined as genetic disorders caused by mutations in single genes. Therefore, one could assume that their mechanisms might be relatively simple, as a defect in one gene should cause the dysfunction of just one protein or functional RNA molecule. However, recent studies have indicated that molecular mechanisms of monogenic diseases are significantly more complicated. The dysfunction of one gene product results not only in the inactivation of just one biochemical reaction, but a network of various reactions is affected. Then, secondary and tertiary effects sometimes lead to the dysregulation of various cellular processes, including the upregulation or downregulation of the expression of many genes, and the disturbance of the physiology of cells, tissues, organs, and whole organisms. We are only at the beginning of understanding the complicated molecular mechanisms of monogenic diseases. The complex character of such diseases is a biological puzzle and causes real problems for the development of effective therapies. The current number of known monogenic diseases is estimated to be about 7000, and only a few can be specifically treated. Moreover, the vast majority of these diseases are severe disorders, and patients suffering from them need novel effective therapies. Development of such therapies is, however, dependent on a detailed understanding of the mechanisms of each disease. Therefore, this Special Issue is focused on research conducted to understand complex molecular mechanisms of monogenic diseases. Both original papers, presenting clinical or experimental studies (using cellular and/or animal models) on understanding the pathomechanisms of such diseases, and review articles, summarizing our knowledge and proposing new hypotheses in the field, are welcome. The submission of papers exploring the unexpected complexity of newly discovered changes occurring as consequences of dysfunctions or dysregulations of single genes is particularly encouraged.

Prof. Dr. Grzegorz Wegrzyn
Guest Editor

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Keywords

  • cystic fibrosis
  • sickle cell disease
  • duchenne muscular dystrophy
  • inherited monogenic disease
  • molecular mechanisms

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Published Papers (5 papers)

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Research

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17 pages, 672 KB  
Article
Genomic Insights into Unspecified Monogenic Forms of Diabetes and Their Associated Comorbidities: Implication for Treatment
by Nadia Kheriji, Hamza Dallali, Mariem Gharbi, Asma Krir, Afef Bahlous, Melika Ben Ahmed, Faten Mahjoub, Abdelmajid Abid, Henda Jamoussi and Rym Kefi
Curr. Issues Mol. Biol. 2025, 47(12), 1055; https://doi.org/10.3390/cimb47121055 - 17 Dec 2025
Viewed by 85
Abstract
This study focuses on the genetic and clinical characterization of Monogenic Forms of Diabetes (MFD), which are frequently underdiagnosed or misclassified due to clinical similarities with type 1 and type 2 diabetes. Researchers performed Exome Sequencing on 11 Tunisian patients suspected of having [...] Read more.
This study focuses on the genetic and clinical characterization of Monogenic Forms of Diabetes (MFD), which are frequently underdiagnosed or misclassified due to clinical similarities with type 1 and type 2 diabetes. Researchers performed Exome Sequencing on 11 Tunisian patients suspected of having MFD. The pathogenicity of genetic variants was assessed using filtering and bioinformatics prediction tools. The ORVAL online tool was used to predict the likelihood of combinations of pathogenic variants. Sanger sequencing confirmed likely pathogenic predicted variants in patients and assessed familial segregation. We identified 15 potentially pathogenic variants in 14 genes linked to MFD, including MODY-3, and isolated diabetes with low penetrance for Wolfram syndrome. Additionally, syndromic forms such as partial familial lipodystrophy types 2 and 4, and Wolfram syndrome were detected. Five patients exhibited characteristics of unspecified MFD. This study underscores the importance of genetic screening in individuals with diabetes who have a family history of the disease, particularly those with associated comorbidities. Our findings emphasize the crucial role of genetic testing in refining diabetes classification, leading to more accurate diagnoses. Therefore, integrating genetic research into clinical practice is essential to improving healthcare outcomes for patients with diabetes. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition)
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10 pages, 2838 KB  
Article
Analysis of Cytosine Base Editors in Bovine Zygotes: Efficiency and Editing Window Characterization Through Targeting the MYO7A Gene
by Junghyun Ryu, Rebecca Tippner-Hedges, Martha Neuringer and Jon D. Hennebold
Curr. Issues Mol. Biol. 2025, 47(12), 1033; https://doi.org/10.3390/cimb47121033 - 11 Dec 2025
Viewed by 157
Abstract
Cytosine base editors (CBEs) enable precise C-to-T (G-to-A) conversions in genomic DNA, offering significant potential for specific gene editing. This study compared the prototypical Base Editor 3 (BE3) and a modified variant, BE3-Y130F, which utilizes an hA3A deaminase with the Y130F mutation, focusing [...] Read more.
Cytosine base editors (CBEs) enable precise C-to-T (G-to-A) conversions in genomic DNA, offering significant potential for specific gene editing. This study compared the prototypical Base Editor 3 (BE3) and a modified variant, BE3-Y130F, which utilizes an hA3A deaminase with the Y130F mutation, focusing on their editing efficiency and editing window characteristics using bovine zygotes. Following in vitro fertilization (IVF), sgRNA and Cas9 mRNA were injected as a targeting efficiency control, which resulted in 100% editing with no wild-type sequence. Then, either BE3 or BE3-Y130F mRNA, synthesized via in vitro transcription, and an sgRNA targeting exon 4 of the MYO7A gene was injected into zygotes. Genomic DNA was extracted from both blastocysts and developmentally arrested embryos, and Sanger sequencing was performed to evaluate C-to-T conversion efficiency and editing window. Both BE3 and BE3-Y130F achieved 100% C-to-T conversion efficiency at the primary target cytosine. BE3 displayed a defined editing window, primarily affecting cytosines at positions 7 and 8, indicating a predictable profile. In contrast, BE3-Y130F maintained high efficiency but had a less clearly defined editing window, resulting in incomplete editing and a remaining cytosine on the target sequence. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition)
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Review

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23 pages, 651 KB  
Review
Beyond the Exome: The Role of Noncoding and Regulatory Variants in Monogenic Diseases
by Efthalia Moustakli, Nektaria Zagorianakou, Stylianos Makrydimas, Andreas Miltiadous, Alexandros T. Tzallas and George Makrydimas
Curr. Issues Mol. Biol. 2025, 47(12), 1038; https://doi.org/10.3390/cimb47121038 - 12 Dec 2025
Viewed by 277
Abstract
Analysis of coding areas has long been used to study monogenic illnesses, but despite the extensive use of whole-exome sequencing (WES), up to half of suspected cases remain genetically unexplained. Variants outside coding areas can alter splicing, transcript stability, or gene regulation, compromising [...] Read more.
Analysis of coding areas has long been used to study monogenic illnesses, but despite the extensive use of whole-exome sequencing (WES), up to half of suspected cases remain genetically unexplained. Variants outside coding areas can alter splicing, transcript stability, or gene regulation, compromising normal gene activity. These include mutations in noncoding RNAs, promoters, enhancers, deep intronic sequences, and untranslated regions (UTRs). Several well-known disorders have been linked to these mechanisms, including β-thalassemia caused by deep intronic mutations leading to aberrant splicing, familial hypercholesterolemia caused by promoter defects affecting LDLR expression, and inherited retinal diseases driven by noncoding variants influencing retinal gene regulation. These instances show that pathogenic variation is not limited to the exome and can have significant clinical implications. This review summarizes current understanding of noncoding and regulatory variants in monogenic diseases, discusses how they influence diagnosis and therapy, and highlights integrative approaches combining genomic, transcriptomic, and epigenomic data. Multi-layered research has increased diagnostic accuracy and unveiled new therapeutic potentials, although noncoding variations make the connection between genotype and phenotype more complex. Noncoding regions will need to be incorporated into standard diagnostic procedures to convert molecular insights into concrete therapeutic applications in the future. Predictive algorithms, patient-derived model systems, and functional validation testing will all help to simplify this process. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition)
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40 pages, 9462 KB  
Review
Unraveling the Mechanism of Action, Binding Sites, and Therapeutic Advances of CFTR Modulators: A Narrative Review
by Debora Baroni
Curr. Issues Mol. Biol. 2025, 47(2), 119; https://doi.org/10.3390/cimb47020119 - 11 Feb 2025
Cited by 6 | Viewed by 13168
Abstract
Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel localized on the plasma membrane of epithelial cells. Over the last three decades, high-throughput screening assays have been [...] Read more.
Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel localized on the plasma membrane of epithelial cells. Over the last three decades, high-throughput screening assays have been extensively employed in identifying drugs that target specific defects arising from CFTR mutations. The two main categories of such compounds are potentiators, which enhance CFTR gating by increasing the channel’s open probability, and correctors, which improve CFTR protein folding and trafficking to the plasma membrane. In addition to these, other investigational molecules include amplifiers and stabilizers, which enhance the levels and the stability of CFTR on the cell surface, and read-through agents that promote the insertion of correct amino acids at premature termination codons. Currently, four CFTR modulators are clinically approved: the potentiator ivacaftor (VX-770), either as monotherapy or in combination with the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Among these, the triple combination VX-445/VX-661/VX-770 (marketed as Trikafta® in the US and Kaftrio® in Europe) has emerged as the most effective CFTR modulator therapy to date, demonstrating significant clinical benefits in phase III trials for patients with at least one F508del CFTR allele. Despite these advancements, the mechanisms of action and binding sites of these modulators on CFTR have only recently begun to be elucidated. A deeper understanding of these mechanisms could provide essential insights for developing more potent and effective modulators, particularly in combination therapies. This narrative review delves into the mechanism of action, binding sites, and combinatorial effects of approved and investigational CFTR modulators, highlighting ongoing efforts to broaden therapeutic options for individuals with CF. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition)
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15 pages, 938 KB  
Review
A New Frontier in Cystic Fibrosis Pathophysiology: How and When Clock Genes Can Affect the Inflammatory/Immune Response in a Genetic Disease Model
by Annalucia Carbone, Pamela Vitullo, Sante Di Gioia, Stefano Castellani and Massimo Conese
Curr. Issues Mol. Biol. 2024, 46(9), 10396-10410; https://doi.org/10.3390/cimb46090618 - 18 Sep 2024
Cited by 1 | Viewed by 4246
Abstract
Cystic fibrosis (CF) is a monogenic syndrome caused by variants in the CF Transmembrane Conductance Regulator (CFTR) gene, affecting various organ and systems, in particular the lung, pancreas, sweat glands, liver, gastrointestinal tract, vas deferens, and vascular system. While for some [...] Read more.
Cystic fibrosis (CF) is a monogenic syndrome caused by variants in the CF Transmembrane Conductance Regulator (CFTR) gene, affecting various organ and systems, in particular the lung, pancreas, sweat glands, liver, gastrointestinal tract, vas deferens, and vascular system. While for some organs, e.g., the pancreas, a strict genotype-phenotype occurs, others, such as the lung, display a different pathophysiologic outcome in the presence of the same mutational asset, arguing for genetic and environmental modifiers influencing severity and clinical trajectory. CFTR variants trigger a pathophysiological cascade of events responsible for chronic inflammatory responses, many aspects of which, especially related to immunity, are not ascertained yet. Although clock genes expression and function are known modulators of the innate and adaptive immunity, their involvement in CF has been only observed in relation to sleep abnormalities. The aim of this review is to present current evidence on the clock genes role in immune-inflammatory responses at the lung level. While information on this topic is known in other chronic airway diseases (chronic obstructive pulmonary disease and asthma), CF lung disease (CFLD) is lacking in this knowledge. We will present the bidirectional effect between clock genes and inflammatory factors that could possibly be implicated in the CFLD. It must be stressed that besides sleep disturbance and its mechanisms, there are not studies directly addressing the exact nature of clock genes’ involvement in inflammation and immunity in CF, pointing out the directions of new and deepened studies in this monogenic affection. Importantly, clock genes have been found to be druggable by means of genetic tools or pharmacological agents, and this could have therapeutic implications in CFLD. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition)
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