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Complex Molecular Mechanism of Monogenic Diseases 2.0

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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 15345

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Prof. Dr. Grzegorz Wegrzyn

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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
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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

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Complex Molecular Mechanism of Monogenic Diseases in Current Issues in Molecular Biology (5 articles)

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Research

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13 pages, 464 KiB

Open AccessArticle

Improving the Yield of Genetic Diagnosis through Additional Genetic Panel Testing in Hereditary Ophthalmic Diseases

by Jin Gwack, Namsu Kim and Joonhong Park

Curr. Issues Mol. Biol. 2024, 46(5), 5010-5022; https://doi.org/10.3390/cimb46050300 - 20 May 2024

Viewed by 920

Abstract

Numerous hereditary ophthalmic diseases display significant genetic diversity. Consequently, the utilization of gene panel sequencing allows a greater number of patients to receive a genetic diagnosis for their clinical manifestations. We investigated how to improve the yield of genetic diagnosis through additional gene panel sequencing in hereditary ophthalmic diseases. A gene panel sequencing consisting of a customized hereditary retinopathy panel or hereditary retinitis pigmentosa (RP) panel was prescribed and referred to a CAP-accredited clinical laboratory. If no significant mutations associated with hereditary retinopathy and RP were detected in either panel, additional gene panel sequencing was requested for research use, utilizing the remaining panel. After additional gene panel sequencing, a total of 16 heterozygous or homozygous variants were identified in 15 different genes associated with hereditary ophthalmic diseases. Of 15 patients carrying any candidate variants, the clinical symptoms could be tentatively accounted for by genetic mutations in seven patients. However, in the remaining eight patients, given the in silico mutation predictive analysis, variant allele frequency in gnomAD, inheritance pattern, and genotype–phenotype correlation, fully elucidating the clinical manifestations with the identified rare variant was challenging. Our study highlights the utility of gene panel sequencing in achieving accurate diagnoses for hereditary ophthalmic diseases and enhancing the diagnostic yield through additional gene panel sequencing. Thus, gene panel sequencing can serve as a primary tool for the genetic diagnosis of hereditary ophthalmic diseases, even in cases where a single genetic cause is suspected. With a deeper comprehension of the genetic mechanisms underlying these diseases, it becomes feasible. Full article

(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)

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23 pages, 4212 KiB

Open AccessArticle

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

Cited by 1 | Viewed by 2229

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 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

Open AccessArticle

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 - 8 Aug 2023

Cited by 3 | Viewed by 1848

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 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

Open AccessArticle

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. 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

Open AccessArticle

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 Danesino Show full author list Hide full author list

Curr. Issues Mol. Biol. 2023, 45(4), 2847-2860; https://doi.org/10.3390/cimb45040186 - 1 Apr 2023

Cited by 2 | Viewed by 2388

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 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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23 pages, 1896 KiB

Open AccessReview

Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment

by Giulia Spoto, Graziana Ceraolo, Ambra Butera, Gabriella Di Rosa and Antonio Gennaro Nicotera

Curr. Issues Mol. Biol. 2024, 46(6), 5632-5654; https://doi.org/10.3390/cimb46060337 - 6 Jun 2024

Viewed by 1270

Abstract

Chorea is a hyperkinetic movement disorder frequently observed in the pediatric population, and, due to advancements in genetic techniques, an increasing number of genes have been associated with this disorder. In genetic conditions, chorea may be the primary feature of the disorder, or be part of a more complex phenotype characterized by epileptic encephalopathy or a multisystemic syndrome. Moreover, it can appear as a persistent disorder (chronic chorea) or have an episodic course (paroxysmal chorea). Managing chorea in childhood presents challenges due to its varied clinical presentation, often involving a spectrum of hyperkinetic movement disorders alongside neuropsychiatric and multisystemic manifestations. Furthermore, during infancy and early childhood, transient motor phenomena resembling chorea occurring due to the rapid nervous system development during this period can complicate the diagnosis. This review aims to provide an overview of the main genetic causes of pediatric chorea that may manifest during infancy and early childhood, focusing on peculiarities that can aid in differential diagnosis among different phenotypes and discussing possible treatment options. Full article

(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)

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14 pages, 586 KiB

Open AccessReview

Role of NR5A1 Gene Mutations in Disorders of Sex Development: Molecular and Clinical Features

by Giovanni Luppino, Malgorzata Wasniewska, Roberto Coco, Giorgia Pepe, Letteria Anna Morabito, Alessandra Li Pomi, Domenico Corica and Tommaso Aversa

Curr. Issues Mol. Biol. 2024, 46(5), 4519-4532; https://doi.org/10.3390/cimb46050274 - 9 May 2024

Viewed by 1351

Abstract

Disorders/differences of sex development (DSDs) are defined as broad, heterogenous groups of congenital conditions characterized by atypical development of genetic, gonadal, or phenotypic sex accompanied by abnormal development of internal and/or external genitalia. NR5A1 gene mutation is one of the principal genetic alterations implicated in causing DSD. This review outlines the role of NR5A1 gene during the process of gonadal development in humans, provides an overview of the molecular and functional characteristics of NR5A1 gene, and discusses potential clinical phenotypes and additional organ diseases due to NR5A1 mutations. NR5A1 mutations were analyzed in patients with 46,XY DSD and 46,XX DSD both during the neonatal and pubertal periods. Loss of function of the NR5A1 gene causes several different phenotypes, including some associated with disease in additional organs. Clinical phenotypes may vary, even among patients carrying the same NR5A1 variant, indicating that there is no specific genotype–phenotype correlation. Genetic tests are crucial diagnostic tools that should be used early in the diagnostic pathway, as early as the neonatal period, when gonadal dysgenesis is the main manifestation of NR5A1 mutation. NR5A1 gene mutations could be mainly associated with amenorrhea, ovarian failure, hypogonadism, and infertility during puberty. Fertility preservation techniques should be considered as early as possible. Full article

(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)

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13 pages, 1803 KiB

Open AccessCase Report

Challenging Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency: Case Series and Novel Variants of CYP21A2 Gene

by Paola Concolino

Curr. Issues Mol. Biol. 2024, 46(5), 4832-4844; https://doi.org/10.3390/cimb46050291 - 16 May 2024

Cited by 2 | Viewed by 1812

Abstract

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has downstream effects. The most common variant of CAH, 21-hydroxylase deficiency (21OHD), is the result of pathogenic variants in the CYP21A2 gene and is one of the most common monogenic disorders. However, the genetics of 21OHD is complex and challenging. The CYP21A2 gene is located in the RCCX copy number variation (CNV), a complex, multiallelic, and tandem CNV in the major histocompatibility complex (MHC) class III region on chromosome 6 (band 6p21.3). Here, CYP21A2 and its pseudogene CYP21A1P are located 30 kb apart and share a high nucleotide homology of approximately 98% and 96% in exons and introns, respectively. This high-sequence homology facilitates large structural rearrangements, copy number changes, and gene conversion through intergenic recombination. There is a good genotype–phenotype correlation in 21OHD, and genotyping can be performed to confirm the clinical diagnosis, predict long-term outcomes, and determine genetic counseling. Thus, genotyping in CAH is clinically relevant but the interpretations can be challenging for non-initiated clinicians. Here, there are some concrete examples of how molecular diagnosis can sometimes require the use of multiple molecular strategies. 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

Open AccessCase 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

Cited by 1 | Viewed by 1068

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. 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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