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Complex Molecular Mechanism of Monogenic Diseases 2.0
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Complex Molecular Mechanism of Monogenic Diseases 2.0

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: closed (31 March 2024) | Viewed by 5945

Special Issue Editor

Prof. Dr. Grzegorz Wegrzyn

E-Mail Website
Guest Editor
Department of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, 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” (https://www.mdpi.com/journal/cimb/special_issues/CIMB_monogenic).

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 dysfunction of just one protein or functional RNA molecule. However, recent studies have indicated that molecular mechanisms of monogenic diseases are significantly more complicated. 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 dysregulation of various cellular processes, including the up- or down-regulation of the expression of many genes, and 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 7,000, 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 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, or newly discovered, changes occurring as consequences of dysfunctions or dysregulations of single genes is particularly encouraged.

Prof. Dr. Grzegorz Wegrzyn
Guest Editor

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. Current Issues in Molecular Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 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.

Related Special Issue

Published Papers (5 papers)

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23 pages, 4212 KiB  
Article
Cellular Organelle-Related Transcriptomic Profile Abnormalities in Neuronopathic Types of Mucopolysaccharidosis: A Comparison with Other Neurodegenerative Diseases
by Karolina Wiśniewska, Lidia Gaffke, Magdalena Żabińska, Grzegorz Węgrzyn and Karolina Pierzynowska
Curr. Issues Mol. Biol. 2024, 46(3), 2678-2700; https://doi.org/10.3390/cimb46030169 - 21 Mar 2024
Viewed by 551
Abstract
Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations in genes encoding lysosomal enzymes that catalyze reactions of glycosaminoglycan (GAG) degradation. As a result, GAGs accumulate in lysosomes, impairing the proper functioning of entire cells and tissues. There are 14 types/subtypes of [...] Read more.
Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations in genes encoding lysosomal enzymes that catalyze reactions of glycosaminoglycan (GAG) degradation. As a result, GAGs accumulate in lysosomes, impairing the proper functioning of entire cells and tissues. There are 14 types/subtypes of MPS, which are differentiated by the kind(s) of accumulated GAG(s) and the type of a non-functional lysosomal enzyme. Some of these types (severe forms of MPS types I and II, MPS III, and MPS VII) are characterized by extensive central nervous system disorders. The aim of this work was to identify, using transcriptomic methods, organelle-related genes whose expression levels are changed in neuronopathic types of MPS compared to healthy cells while remaining unchanged in non-neuronopathic types of MPS. The study was conducted with fibroblast lines derived from patients with neuronopathic and non-neuronopathic types of MPS and control (healthy) fibroblasts. Transcriptomic analysis has identified genes related to cellular organelles whose expression is altered. Then, using fluorescence and electron microscopy, we assessed the morphology of selected structures. Our analyses indicated that the genes whose expression is affected in neuronopathic MPS are often associated with the structures or functions of the cell nucleus, endoplasmic reticulum, or Golgi apparatus. Electron microscopic studies confirmed disruptions in the structures of these organelles. Special attention was paid to up-regulated genes, such as PDIA3 and MFGE8, and down-regulated genes, such as ARL6IP6, ABHD5, PDE4DIP, YIPF5, and CLDN11. Of particular interest is also the GM130 (GOLGA2) gene, which encodes golgin A2, which revealed an increased expression in neuronopathic MPS types. We propose to consider the levels of mRNAs of these genes as candidates for biomarkers of neurodegeneration in MPS. These genes may also become potential targets for therapies under development for neurological disorders associated with MPS and candidates for markers of the effectiveness of these therapies. Although fibroblasts rather than nerve cells were used in this study, it is worth noting that potential genetic markers characteristic solely of neurons would be impractical in testing patients, contrary to somatic cells that can be relatively easily obtained from assessed persons. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)
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12 pages, 2697 KiB  
Article
Aging Aggravates Periodontal Inflammatory Responses and Alveolar Bone Resorption by Porphyromonas gingivalis Infection
by Yuri Song and Jin Chung
Curr. Issues Mol. Biol. 2023, 45(8), 6593-6604; https://doi.org/10.3390/cimb45080416 - 08 Aug 2023
Viewed by 1247
Abstract
Periodontitis is a chronic inflammatory disease driven by periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis), and its prevalence increases with age. However, little is known about the effect of immunosenescence on inflammatory response to P. gingivalis infection. In the present study, 16S rDNA [...] Read more.
Periodontitis is a chronic inflammatory disease driven by periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis), and its prevalence increases with age. However, little is known about the effect of immunosenescence on inflammatory response to P. gingivalis infection. In the present study, 16S rDNA sequencing analysis showed the relative abundance of P. gingivalis was significantly higher in periodontitis patients than healthy group, but there was no difference between the young (20 to 40 years old) and old (65 to 86 years old) periodontitis groups. Furthermore, the cytotoxic effect of P. gingivalis was greater on old THP-1 macrophages and on bone mar-row-derived cells (BMDMs) from old mice, and levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-12 were higher in old than in young THP-1 macrophages. Furthermore, the activations of inflammasome components for IL-1β production by P. gingivalis infection were greater in old THP-1 macrophages. Finally, bone loss was significantly greater in P. gingivalis-infected aged mice than in young mice. These findings indicate that aging aggravates P. gingivalis-induced inflammatory cytokine secretion and inflammasome activation. The study enhances understanding of the relationship between periodontal immunosenescence and inflammatory response in the elderly. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)
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13 pages, 600 KiB  
Article
HLA-G Alleles Impact the Perinatal Father–Child HPV Transmission
by Nelli T. Suominen, Michel Roger, Marie-Claude Faucher, Kari J. Syrjänen, Seija E. Grénman, Stina M. Syrjänen and Karolina Louvanto
Curr. Issues Mol. Biol. 2023, 45(7), 5798-5810; https://doi.org/10.3390/cimb45070366 - 12 Jul 2023
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Abstract
The host factors that influence father-to-child human papillomavirus (HPV) transmission remain unknown. This study evaluated whether human leukocyte antigen (HLA)-G alleles are important in father-to-child HPV transmission during the perinatal period. Altogether, 134 father–newborn pairs from the Finnish Family HPV Study were included. [...] Read more.
The host factors that influence father-to-child human papillomavirus (HPV) transmission remain unknown. This study evaluated whether human leukocyte antigen (HLA)-G alleles are important in father-to-child HPV transmission during the perinatal period. Altogether, 134 father–newborn pairs from the Finnish Family HPV Study were included. Oral, semen and urethral samples from the fathers were collected before the delivery, and oral samples were collected from their offspring at delivery and postpartum on day 3 and during 1-, 2- and 6-month follow-up visits. HLA-G alleles were tested by direct sequencing. Unconditional logistic regression was used to determine the association of the father–child HLA-G allele and genotype concordance with the father–child HPV prevalence and concordance at birth and during follow-up. HLA-G allele G*01:01:03 concordance was associated with the father’s urethral and child’s oral high-risk (HR)-HPV concordance at birth (OR 17.00, 95% CI: 1.24–232.22). HLA-G allele G*01:04:01 concordance increased the father’s oral and child’s postpartum oral any- and HR-HPV concordance with an OR value of 7.50 (95% CI: 1.47–38.16) and OR value of 7.78 (95% CI: 1.38–43.85), respectively. There was no association between different HLA-G genotypes and HPV concordance among the father–child pairs at birth or postpartum. To conclude, the HLA-G allele concordance appears to impact the HPV transmission between the father and his offspring. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)
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14 pages, 458 KiB  
Article
Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)
by Paola De Filippi, Edoardo Errichiello, Antonio Toscano, Tiziana Mongini, Maurizio Moggio, Sabrina Ravaglia, Massimiliano Filosto, Serenella Servidei, Olimpia Musumeci, Fabio Giannini, Alberto Piperno, Gabriele Siciliano, Giulia Ricci, Antonio Di Muzio, Miriam Rigoldi, Paola Tonin, Michele Giovanni Croce, Elena Pegoraro, Luisa Politano, Lorenzo Maggi, Roberta Telese, Alberto Lerario, Cristina Sancricca, Liliana Vercelli, Claudio Semplicini, Barbara Pasanisi, Bruno Bembi, Andrea Dardis, Ilaria Palmieri, Cristina Cereda, Enza Maria Valente and Cesare Danesinoadd Show full author list remove Hide full author list
Curr. Issues Mol. Biol. 2023, 45(4), 2847-2860; https://doi.org/10.3390/cimb45040186 - 01 Apr 2023
Cited by 2 | Viewed by 1767
Abstract
Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed, and caution is [...] Read more.
Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)

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10 pages, 584 KiB  
Case Report
An Unusual Presentation of Novel Missense Variant in PAX6 Gene: NM_000280.4:c.341A>G, p.(Asn114Ser)
by Tatyana A. Vasilyeva, Natella V. Sukhanova, Olga V. Khalanskaya, Andrey V. Marakhonov, Nikolai S. Prokhorov, Vitaly V. Kadyshev, Nikolay A. Skryabin, Sergey I. Kutsev and Rena A. Zinchenko
Curr. Issues Mol. Biol. 2024, 46(1), 96-105; https://doi.org/10.3390/cimb46010008 - 22 Dec 2023
Viewed by 649
Abstract
This study investigates a unique and complex eye phenotype characterized by minimal iris defects, foveal hypoplasia, optic nerve coloboma, and severe posterior segment damage. Through genetic analysis and bioinformatic tools, a specific nonsynonymous substitution, p.(Asn114Ser), within the PAX6 gene’s paired domain is identified. [...] Read more.
This study investigates a unique and complex eye phenotype characterized by minimal iris defects, foveal hypoplasia, optic nerve coloboma, and severe posterior segment damage. Through genetic analysis and bioinformatic tools, a specific nonsynonymous substitution, p.(Asn114Ser), within the PAX6 gene’s paired domain is identified. Although this substitution is not in direct contact with DNA, its predicted stabilizing effect on the protein structure challenges the traditional understanding of PAX6 mutations, suggesting a gain-of-function mechanism. Contrary to classical loss-of-function effects, this gain-of-function hypothesis aligns with research demonstrating PAX6’s dosage sensitivity. Gain-of-function mutations, though less common, can lead to diverse phenotypes distinct from aniridia. Our findings emphasize PAX6’s multifaceted influence on ocular phenotypes and the importance of genetic variations. We contribute a new perspective on PAX6 mutations by suggesting a potential gain-of-function mechanism and showcasing the complexities of ocular development. This study sheds light on the intricate interplay of the genetic alterations and regulatory mechanisms underlying complex eye phenotypes. Further research, validation, and collaboration are crucial to unravel the nuanced interactions shaping ocular health and development. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)
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