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Complex Molecular Mechanism of Monogenic Diseases

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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 9899

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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，

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 2.0 in Current Issues in Molecular Biology (5 articles)

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17 pages, 1532 KiB

Open AccessArticle

Genetic and Epigenetic Regulation of MEFV Gene and Their Impact on Clinical Outcome in Auto-Inflammatory Familial Mediterranean Fever Patients

by May E. Zekry, Al-Aliaa M. Sallam, Sherihan G. AbdelHamid, Waheba A. Zarouk, Hala T. El-Bassyouni and Hala O. El-Mesallamy

Curr. Issues Mol. Biol. 2023, 45(1), 721-737; https://doi.org/10.3390/cimb45010048 - 13 Jan 2023

Cited by 2 | Viewed by 2614

Abstract

Epigenetic modifications play a pivotal role in autoimmune/inflammatory disorders and could establish a bridge between personalized medicine and disease epidemiological contexts. We sought to investigate the role of epigenetic modifications beside genetic alterations in the MEFV gene in familial Mediterranean fever (FMF). The study comprised 63 FMF patients diagnosed according to the Tel Hashomer criteria: 37 (58.7%) colchicine-responders, 26 (41.3%) non-responders, and 19 matched healthy controls. MEFV mutations were detected using a CE/IVD-labeled 4-230 FMF strip assay. DNA methylation of MEFV gene exon 2 was measured using bisulfite modification and related to pyrin level, phenotypic picture, MEFV mutations, disease severity, serum amyloid A (SAA), CRP, ESR, disease severity, and colchicine response. Our results showed that FMF patients exhibited significantly higher methylation percentage (p < 0.001) and lower pyrin levels (p < 0.001) compared to the control. The MEFV gene M694I mutation was the most commonly reported mutation (p < 0.004). High methylation percentage of the MEFV exon 2 and low pyrin concentration were correlated with disease severity, high SAA, ESR levels, H-pylori, and renal calculi. In conclusion, this study highlights the relation between high methylation percentage, reduced pyrin level, and different biomarkers in FMF, which underscores their role in the pathogenesis of FMF and could be considered as potential therapeutic targets. Full article

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

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14 pages, 751 KiB

Open AccessArticle

OPA1 Dominant Optic Atrophy: Diagnostic Approach in the Pediatric Population

by Natalia Arruti, Patricia Rodríguez-Solana, María Nieves-Moreno, Marta Guerrero-Carretero, Ángela del Pozo, Victoria E. F. Montaño, Fernando Santos-Simarro, Emi Rikeros-Orozco, Luna Delgado-Mora, Elena Vallespín and Susana Noval

Curr. Issues Mol. Biol. 2023, 45(1), 465-478; https://doi.org/10.3390/cimb45010030 - 05 Jan 2023

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Abstract

A clinical and genetic study was conducted with pediatric patients and their relatives with optic atrophy 1 (OPA1) mutations to establish whether there is a genotype–phenotype correlation among the variants detected within and between families. Eleven children with a confirmed OPA1 mutation were identified during the study period. The main initial complaint was reduced visual acuity (VA), present in eight patients of the cohort. Eight of eleven patients had a positive family history of optic atrophy. The mean visual acuity at the start of the study was 0.40 and 0.44 LogMAR in the right and left eye, respectively. At the end of the study, the mean visual acuity was unchanged. Optical coherence tomography during the first visit showed a mean retinal nerve fiber layer thickness of 81.6 microns and 80.5 microns in the right and left eye, respectively; a mean ganglion cell layer of 52.5 and 52.4 microns, respectively, and a mean central macular thickness of 229.5 and 233.5 microns, respectively. The most common visual field defect was a centrocecal scotoma, and nine out of eleven patients showed bilateral temporal disc pallor at baseline. Sequencing of OPA1 showed seven different mutations in the eleven patients, one of which, NM_130837.3: c.1406_1407del (p.Thr469LysfsTer16), has not been previously reported. Early diagnosis of dominant optic atrophy is crucial, both for avoiding unnecessary consultations and/or treatments and for appropriate genetic counseling. Full article

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

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13 pages, 5018 KiB

Open AccessArticle

Personalized Selection of a CFTR Modulator for a Patient with a Complex Allele [L467F;F508del]

by Elena Kondratyeva, Nataliya Bulatenko, Yuliya Melyanovskaya, Anna Efremova, Elena Zhekaite, Viktoriya Sherman, Anna Voronkova, Irina Asherova, Alexander Polyakov, Tagui Adyan, Valeriia Kovalskaia, Tatiana Bukharova, Dmitry Goldshtein and Sergey Kutsev

Curr. Issues Mol. Biol. 2022, 44(10), 5126-5138; https://doi.org/10.3390/cimb44100349 - 21 Oct 2022

Cited by 6 | Viewed by 1766

Abstract

The presence of complex alleles in the CFTR gene can lead to difficulties in diagnosing cystic fibrosis and cause resistance to therapy with CFTR modulators. Tezacaftor/ivacaftor therapy for 8 months in a patient with the initially established F508del/F508del genotype did not lead to an improvement in her condition—there was no change in spirometry and an increase in the patient’s weight, while there was only a slight decrease in NaCl values, measured by a sweat test. The intestinal current measurements of the patient’s rectal biopsy showed no positive dynamics in the rescue of CFTR function while taking tezacaftor/ivacaftor. The assumption that the patient had an additional mutation in the cis position was confirmed by sequencing the CFTR gene, and the complex allele [L467F;F508del] was identified. Based on the rescue of CFTR function by elexacaftor/tezacaftor/ivacaftor obtained using forskolin-induced swelling on intestinal organoids, the patient was prescribed therapy with this targeted drug. The use of elexacaftor/tezacaftor/ivacaftor for 7 months resulted in a significant improvement in the patient’s clinical condition. Full article

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

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13 pages, 1999 KiB

Open AccessArticle

The Leucocyte Telomere Length, GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease

by Tanya Tacheva, Shanbeh Zienolddiny-Narui, Dimo Dimov, Denitsa Vlaykova, Iva Miteva and Tatyana Vlaykova

Curr. Issues Mol. Biol. 2022, 44(8), 3757-3769; https://doi.org/10.3390/cimb44080257 - 20 Aug 2022

Cited by 1 | Viewed by 1658

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD. Full article

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

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7 pages, 1338 KiB

Open AccessCase Report

The First Homozygote Mutation c.499G>T (Asp167Tyr) in the RPE65 Gene Encoding Retinoid Isomerohydrolase Causing Retinal Dystrophy

by Mirjana Bjeloš, Ana Ćurić, Benedict Rak, Mladen Bušić and Biljana Kuzmanović Elabjer

Curr. Issues Mol. Biol. 2022, 44(12), 6397-6403; https://doi.org/10.3390/cimb44120436 - 16 Dec 2022

Viewed by 1188

Abstract

RPE65, an abundant membrane-associated protein present in the retinal pigment epithelium (RPE), is a vital retinoid isomerase necessary for regenerating 11-cis-retinaldehyde from all-trans retinol in the visual cycle. In patients with inherited retinal dystrophy (IRD), precise genetic diagnosis is an indispensable approach as it is required to establish eligibility for the genetic treatment of RPE65-associated IRDs. This case report aims to report the specific phenotype–genotype correlation of the first patient with a homozygous missense variant RPE65 c.499G>T, p. (Asp167Tyr). We report a case of a 66-year-old male who demonstrated a unique phenotype manifesting less severe functional vision deterioration in childhood and adolescence, and extensive nummular pigment clusters. The underlying causes of the differences in the typical bone spicule and atypical nummular pigment clumping are unknown, but suggest that the variant itself influenced the rate of photoreceptor death. Functional studies are needed to define whether the substitution of aspartate impairs the folding of the tertiary RPE65 structure only and does not lead to the complete abolishment of chromophore production, thus explaining the less severe phenotype in adolescence. Full article

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

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