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Genetic Mutations in Health and Disease
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Genetic Mutations in Health and Disease

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

Deadline for manuscript submissions: 26 May 2025 | Viewed by 4651

Special Issue Editor

Dr. Eva Bagyinszky

E-Mail Website
Guest Editor
Graduate School of Environment, Department of Industrial and Environmental Engineering, Gachon University, Seongnam 13120, Republic of Korea
Interests: genetics; neurology; mutation; gene interactions; structure predictions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genetics play a significant role in the onset and progression of many diseases. While some genetic diseases are caused by mutations in a single gene, many others are associated with multiple genetic factors. Additionally, environmental influences often interplay with genetic predispositions, contributing to the complexity of these diseases.

This Special Issue focuses on the genetic underpinnings of human diseases, including cancer, neurodegenerative disorders, and metabolic conditions. Our aim is to explore the various aspects of genetic mutations, environmental factors, disease diagnosis, and management strategies. Despite advancements in medical science, the treatment of many genetic diseases remains challenging, as effective therapies are still lacking for several conditions. However, gene therapy presents a promising avenue for disease management and potential cures.

We invite the submission of review articles, research articles, and case reports that address these topics. Through this collection, we hope to advance our understanding of the genetic basis of diseases and contribute to the development of innovative diagnostic and therapeutic approaches.

Dr. Eva Bagyinszky
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.

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Keywords

  • genetic diseases
  • mutations
  • genetic screening
  • structure prediction
  • haploinsufficeincy
  • germline mutations
  • somatic mutations
  • gene enviroment interaction
  • gene-gene interations

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Published Papers (5 papers)

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Research

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13 pages, 2473 KiB  
Article
Identification of Four New Mutations in the GLA Gene Associated with Anderson–Fabry Disease
by Monia Anania, Federico Pieruzzi, Irene Giacalone, Barbara Trezzi, Emanuela Maria Marsana, Letizia Roggero, Daniele Francofonte, Michele Stefanoni, Martina Vinci, Carmela Zizzo, Marcomaria Zora, Tiziana Di Chiara, Giulia Duro, Giovanni Duro and Paolo Colomba
Int. J. Mol. Sci. 2025, 26(2), 473; https://doi.org/10.3390/ijms26020473 - 8 Jan 2025
Viewed by 484
Abstract
Anderson–Fabry disease is a hereditary, progressive, multisystemic lysosomal storage disorder caused by a functional deficiency of the enzyme α-galactosidase A (α-GalA). This defect is due to mutations in the GLA gene, located in the long arm of the X chromosome (Xq21-22). Functional deficiency [...] Read more.
Anderson–Fabry disease is a hereditary, progressive, multisystemic lysosomal storage disorder caused by a functional deficiency of the enzyme α-galactosidase A (α-GalA). This defect is due to mutations in the GLA gene, located in the long arm of the X chromosome (Xq21-22). Functional deficiency of the α-GalA enzyme leads to reduced degradation and accumulation of its substrates, predominantly globotriaosylceramide (Gb3), which accumulate in the lysosomes of numerous cell types, giving rise to the symptomatology. Clinical diagnosis can still be difficult today due to the peculiarities of the disease, which presents with clinical manifestations that overlap with those of other pathologies and a wide possibility of differential diagnoses, which lead to missed diagnoses, misdiagnosis, or a diagnostic delay. Patients with clinical suspicion of Fabry disease undergo a diagnostic workup that includes an evaluation of α-GALA enzyme activity, genetic analysis of the GLA gene, and the measurement of blood Lyso-Gb3, a soluble derivative of Gb3. In this paper, we describe four novel mutations identified in the GLA gene which are associated with absent or reduced α-GalA activity, pathological accumulation of the specific substrate, and characteristic clinical manifestations of Fabry disease. We identified two mutations (c.583insGAATA and p.Y207X) that result in the formation of a premature translation stop codon, resulting in a truncated protein and thus a completely non-functional enzyme. The other two identified gene alterations (p.G261C and c.786G>T, which determine p.W262C) are missense mutations that cause reduced α-GALA activity, the accumulation of blood Lyso-Gb3, and symptoms consistent with Fabry disease, and therefore may be associated with this disorder. The identification of these new mutations in patients with symptoms attributable to Fabry disease increases the molecular knowledge of the GLA gene and provides important support to the clinician, for a more accurate and timely diagnosis of the pathology. Full article
(This article belongs to the Special Issue Genetic Mutations in Health and Disease)
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10 pages, 1260 KiB  
Article
The Identification of a Novel Pathogenic Variant of the GLA Gene Associated with a Classic Phenotype of Anderson–Fabry Disease: A Clinical and Molecular Study
by Irene Giacalone, Luigina Ruzzi, Monia Anania, Mariateresa Cuonzo, Emanuela Maria Marsana, Silvia Mastrippolito, Daniele Francofonte, Silvia Bucco, Annalisa D’Errico, Maria Olimpia Longo, Carmela Zizzo, Luigia Iarlori, Giovanni Duro and Paolo Colomba
Int. J. Mol. Sci. 2025, 26(2), 470; https://doi.org/10.3390/ijms26020470 - 8 Jan 2025
Viewed by 496
Abstract
Anderson–Fabry (or Fabry) disease is a rare lysosomal storage disorder caused by a functional deficiency of the enzyme alpha-galactosidase A. The partial or total defect of this lysosomal enzyme, which is caused by variants in the GLA gene, leads to the accumulation of [...] Read more.
Anderson–Fabry (or Fabry) disease is a rare lysosomal storage disorder caused by a functional deficiency of the enzyme alpha-galactosidase A. The partial or total defect of this lysosomal enzyme, which is caused by variants in the GLA gene, leads to the accumulation of glycosphingolipids, mainly globotriaosylceramide in the lysosomes of different cell types. The clinical presentation of Fabry disease is multisystemic and can vary depending on the specific genetic variants associated with the disease. To date, more than 1000 different variants have been identified in the human GLA gene, including missense and nonsense variants, as well as small and large insertions or deletions. The identification of novel variants in individuals exhibiting symptoms indicative of Fabry disease, expands the molecular comprehension of the GLA gene, providing invaluable insights to physicians in the diagnosis of the disease. In this article, we present the case of two members of the same family, mother and son, in whom a new pathogenic variant was identified. This variant has not been previously described in the literature and is not present in databases. The two family members presented with a number of typical clinical manifestations of the disease, including cornea verticillata, neuropathic pain, left ventricular hypertrophy, angiokeratomas and abdominal pain. The son, but not his mother, showed reduced alpha-galactosidase A activity, while high levels of Lyso-Gb3 in the blood, a specific substrate accumulation biomarker, were found in both. Sequencing of the GLA gene revealed the presence of a variant, c.484delT, which is characterised by the deletion of a single nucleotide, a thymine, in exon 3 of the gene. This results in a frameshift variant, which introduces a premature stop codon, thereby generating a truncated and consequently non-functional protein. Therefore, the clinical and laboratory data indicate that the novel p.W162Gfs*3 variant described herein is associated with the classical form of Fabry disease. Full article
(This article belongs to the Special Issue Genetic Mutations in Health and Disease)
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15 pages, 1752 KiB  
Article
Non-Susceptibility Gene Variants in Head and Neck Paragangliomas
by Anastasiya V. Snezhkina, Vladislav S. Pavlov, George S. Krasnov, Dmitry V. Kalinin, Elena A. Pudova, Olga V. Stolbovskaya, Anastasiya V. Dunshina, Maria S. Fedorova and Anna V. Kudryavtseva
Int. J. Mol. Sci. 2024, 25(23), 12762; https://doi.org/10.3390/ijms252312762 - 27 Nov 2024
Viewed by 900
Abstract
Head and neck paragangliomas (HNPGLs) are rare neoplasms that, along with pheochromocytomas and extra-adrenal paragangliomas, are associated with inherited mutations in at least 12 susceptibility genes in approximately 40% of cases. However, due to the rarity of HNPGLs, only a series of small-scale [...] Read more.
Head and neck paragangliomas (HNPGLs) are rare neoplasms that, along with pheochromocytomas and extra-adrenal paragangliomas, are associated with inherited mutations in at least 12 susceptibility genes in approximately 40% of cases. However, due to the rarity of HNPGLs, only a series of small-scale studies and individual cases have reported mutations in additional genes that may be involved in tumorigenesis. Consequently, numerous disease-causing mutations and genes responsible for the pathogenesis of HNPGLs remain poorly investigated. The aim of this study was to gain a deeper understanding of the genetic basis of HNPGLs by focusing on variants in genes that were not previously identified as well-known drivers. A whole-exome data analysis was conducted on a representative set of 152 HNPGLs. In 30% of the tumors examined, 53 potentially deleterious variants were identified in 36 different genes. The analysis identified pathogenic or likely pathogenic variants in the ARNT, IDH2, L2HGDH, MYH3, PIK3CA, and TERT genes. A functional network analysis of the mutated genes revealed numerous associations and a list of metabolic pathways (e.g., the TCA cycle, carbon metabolism, pyruvate metabolism, etc.) and signaling pathways (e.g., HIF1, PI3K-Akt, FoxO, AMPK, MAPK, etc.) that may play an important role in the development of HNPGLs. The identified range of genetic alterations affecting multiple genes and, potentially, influencing diverse cellular pathways provides an enhanced molecular genetic characterization of HNPGLs. Full article
(This article belongs to the Special Issue Genetic Mutations in Health and Disease)
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16 pages, 2535 KiB  
Article
The Avoidance of Purine Stretches by Cancer Mutations
by Aleksandr V. Vikhorev, Ivan V. Savelev, Oksana O. Polesskaya, Michael M. Rempel, Richard A. Miller, Alexandre A. Vetcher and Max Myakishev-Rempel
Int. J. Mol. Sci. 2024, 25(20), 11050; https://doi.org/10.3390/ijms252011050 - 15 Oct 2024
Viewed by 877
Abstract
Purine stretches, sequences of adenine (A) and guanine (G) in DNA, play critical roles in binding regulatory protein factors and influence gene expression by affecting DNA folding. This study investigates the relationship between purine stretches and cancer development, considering the aromaticity of purines, [...] Read more.
Purine stretches, sequences of adenine (A) and guanine (G) in DNA, play critical roles in binding regulatory protein factors and influence gene expression by affecting DNA folding. This study investigates the relationship between purine stretches and cancer development, considering the aromaticity of purines, quantified by methods like Hückel’s rule and NICS calculations, and the importance of the flanking sequence context. A pronounced avoidance of long purine stretches by typical cancer mutations was observed in public data on the intergenic regions of cancer patients, suggesting a role of intergenic sequences in chromatin reorganization and gene regulation. A statistically significant shortening of purine stretches in cancerous tumors (p value < 0.0001) was found. The insights into the aromatic nature of purines and their stacking energies explain the role of purine stretches in DNA structure, contributing to their role in cancer progression. This research lays the groundwork for understanding the nature of purine stretches, emphasizing their importance in gene regulation and chromatin restructuring, and offers potential avenues for novel cancer therapies and insights into cancer etiology. Full article
(This article belongs to the Special Issue Genetic Mutations in Health and Disease)
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Review

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26 pages, 3159 KiB  
Review
Haploinsufficiency and Alzheimer’s Disease: The Possible Pathogenic and Protective Genetic Factors
by Eva Bagyinszky and Seong Soo A. An
Int. J. Mol. Sci. 2024, 25(22), 11959; https://doi.org/10.3390/ijms252211959 - 7 Nov 2024
Viewed by 1510
Abstract
Alzheimer’s disease (AD) is a complex neurodegenerative disorder influenced by various genetic factors. In addition to the well-established amyloid precursor protein (APP), Presenilin-1 (PSEN1), Presenilin-2 (PSEN2), and apolipoprotein E (APOE), several other genes such as [...] Read more.
Alzheimer’s disease (AD) is a complex neurodegenerative disorder influenced by various genetic factors. In addition to the well-established amyloid precursor protein (APP), Presenilin-1 (PSEN1), Presenilin-2 (PSEN2), and apolipoprotein E (APOE), several other genes such as Sortilin-related receptor 1 (SORL1), Phospholipid-transporting ATPase ABCA7 (ABCA7), Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), Phosphatidylinositol-binding clathrin assembly protein (PICALM), and clusterin (CLU) were implicated. These genes contribute to neurodegeneration through both gain-of-function and loss-of-function mechanisms. While it was traditionally thought that heterozygosity in autosomal recessive mutations does not lead to disease, haploinsufficiency was linked to several conditions, including cancer, autism, and intellectual disabilities, indicating that a single functional gene copy may be insufficient for normal cellular functions. In AD, the haploinsufficiency of genes such as ABCA7 and SORL1 may play significant yet under-explored roles. Paradoxically, heterozygous knockouts of PSEN1 or PSEN2 can impair synaptic plasticity and alter the expression of genes involved in oxidative phosphorylation and cell adhesion. Animal studies examining haploinsufficient AD risk genes, such as vacuolar protein sorting-associated protein 35 (VPS35), sirtuin-3 (SIRT3), and PICALM, have shown that their knockout can exacerbate neurodegenerative processes by promoting amyloid production, accumulation, and inflammation. Conversely, haploinsufficiency in APOE, beta-secretase 1 (BACE1), and transmembrane protein 59 (TMEM59) was reported to confer neuroprotection by potentially slowing amyloid deposition and reducing microglial activation. Given its implications for other neurodegenerative diseases, the role of haploinsufficiency in AD requires further exploration. Modeling the mechanisms of gene knockout and monitoring their expression patterns is a promising approach to uncover AD-related pathways. However, challenges such as identifying susceptible genes, gene–environment interactions, phenotypic variability, and biomarker analysis must be addressed. Enhancing model systems through humanized animal or cell models, utilizing advanced research technologies, and integrating multi-omics data will be crucial for understanding disease pathways and developing new therapeutic strategies. Full article
(This article belongs to the Special Issue Genetic Mutations in Health and Disease)
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