scholarly journals Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms

2021 ◽  
Vol 22 (2) ◽  
pp. 911
Author(s):  
Megan Schmit ◽  
Anja-Katrin Bielinsky
Keyword(s):  
Dna Replication ◽  
Genomic Instability ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Chromosomal Anomalies ◽  
Congenital Diseases ◽  
Clinical Phenotypes ◽  
Pathogenic Variants ◽  
Dna Alterations ◽  
Functional Mechanisms

Deoxyribonucleic acid (DNA) replication can be divided into three major steps: initiation, elongation and termination. Each time a human cell divides, these steps must be reiteratively carried out. Disruption of DNA replication can lead to genomic instability, with the accumulation of point mutations or larger chromosomal anomalies such as rearrangements. While cancer is the most common class of disease associated with genomic instability, several congenital diseases with dysfunctional DNA replication give rise to similar DNA alterations. In this review, we discuss all congenital diseases that arise from pathogenic variants in essential replication genes across the spectrum of aberrant replisome assembly, origin activation and DNA synthesis. For each of these conditions, we describe their clinical phenotypes as well as molecular studies aimed at determining the functional mechanisms of disease, including the assessment of genomic stability. By comparing and contrasting these diseases, we hope to illuminate how the disruption of DNA replication at distinct steps affects human health in a surprisingly cell-type-specific manner.

The Variable Expression of a Novel MBD5 Gene Frameshift Mutation in an Italian Family

2020 ◽  
Author(s):  
Alfredo Orrico ◽  
Lucia Galli ◽  
Maja Rossi ◽  
Ambra Cortesi ◽  
Marta Mazzi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Novel Mutation ◽  
Point Mutations ◽  
Autism Spectrum ◽  
Cognitive Disability ◽  
Dominant Type ◽  
Variable Expression ◽  
Large Deletions ◽  
Pathogenic Variants ◽  
Autosomal Dominant Type

AbstractHaploinsufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene is reported as a cause of an autosomal dominant type of cognitive disability (MRD1) and autism spectrum disorder through large deletions involving multiple genes or point mutations, ultimately leading to haploinsufficiency in both cases. However, relatively few reports have been published on the phenotypical spectrum resulting from point mutations.We report here on a novel heterozygous frameshift variant in the MBD5 gene [c.2579del; p.(Lys860Argfs*11)] in a family in which the typical signs associated with pathogenic variants were expressed with different degrees of severity in the clinical presentation of the carrier individuals.Our findings, adding a novel mutation to the mutational spectrum, further support the relevance of the MBD5 gene as one of the main molecular mechanisms involved in the pathogenesis of intellectual disability and contribute to the characterization of the genotype–phenotype correlations.

scholarly journals Multiple Molecular Targets Associated with Genomic Instability in Lung Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Giovanny Soca-Chafre ◽  
Angelica Montiel-Dávalos ◽  
Inti Alberto De La Rosa-Velázquez ◽  
Claudia Haydeé Saraí Caro-Sánchez ◽  
Adriana Peña-Nieves ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Genomic Instability ◽  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Point Mutations ◽  
Number Variation ◽  
Never Smokers ◽  
Diagnosis Therapy ◽  
Tobacco Carcinogens

Lung cancer (LC) is the first cause of cancer-related deaths worldwide. Elucidating the pathogenesis of LC will give information on key elements of tumor initiation and development while helping to design novel targeted therapies. LC is an heterogeneous disease that has the second highest mutation rate surpassed only by melanoma, since 90% of LC occurs in tobacco smokers. However, only a small percent of smokers develops LC, indicating an inherent genomic instability. Additionally, LC in never smokers suggests other molecular mechanisms not causally linked to tobacco carcinogens. This review presents a current outlook of the connection between LC and genomic instability at the molecular and clinical level summarizing its implications for diagnosis, therapy, and prognosis. The genomic landscape of LC shows widespread alterations such as DNA methylation, point mutations, copy number variation, chromosomal translocations, and aneuploidy. Genome maintenance mechanisms including cell cycle control, DNA repair, and mitotic checkpoints open a window to translational research for finding novel diagnostic biomarkers and targeted therapies in LC.

scholarly journals H3.1K27me1 maintains transcriptional silencing and genome stability by preventing GCN5-mediated histone acetylation

2020 ◽  
Author(s):  
Jie Dong ◽  
Chantal LeBlanc ◽  
Axel Poulet ◽  
Benoit Mermaz ◽  
Gonzalo Villarino ◽  
...  
Keyword(s):  
Dna Replication ◽  
Histone Acetylation ◽  
Genomic Instability ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Histone Acetyltransferase ◽  
Transcriptional Silencing ◽  
Histone Acetyltransferase Gcn5 ◽  
Lysine Residues

AbstractIn plants, genome stability is maintained during DNA replication by the H3.1K27 methyltransferases ATXR5 and ATXR6, which catalyze the deposition of K27me1 on replicationdependent H3.1 variants. Loss of H3.1K27me1 in atxr5 atxr6 double mutants leads to heterochromatin defects, including transcriptional de-repression and genomic instability, but the molecular mechanisms involved remain largely unknown. In this study, we identified the conserved histone acetyltransferase GCN5 as a mediator of transcriptional de-repression and genomic instability in the absence of H3.1K27me1. GCN5 is part of a SAGA-like complex in plants that requires ADA2b and CHR6 to mediate the heterochromatic defects of atxr5 atxr6 mutants. Our results show that Arabidopsis GCN5 acetylates multiple lysine residues on H3.1 variants in vitro, but that H3.1K27 and H3.1K36 play key roles in inducing genomic instability in the absence of H3.1K27me1. Overall, this work reveals a key molecular role for H3.1K27me1 in maintaining genome stability by restricting histone acetylation in plants.

Multiple mechanisms account for genomic instability and molecular mutation in neoplastic transformation

1995 ◽  
Vol 41 (5) ◽  
pp. 644-657 ◽  
Author(s):  
W B Coleman ◽  
G J Tsongalis
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Dna Replication ◽  
Genomic Instability ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Neoplastic Transformation ◽  
Molecular Alteration ◽  
Cellular Processes ◽  
Genes Encoding

Abstract Neoplastic cells typically possess numerous genomic mutations and chromosomal aberrations, including point mutations, gene amplifications and deletions, and replication errors. Acquisition of such genomic instability may represent an early step in the process of carcinogenesis. Proteins involved in DNA replication, DNA repair, cell cycle progression, and others are all components of complex overlapping biochemical pathways that function to maintain cellular homeostasis. Therefore, mutational alteration of genes encoding proteins involved in these cellular processes could contribute to genomic instability. Loss of normal cellular mechanisms that guard against genomic mutation and the ensuing genomic instability might lead to accumulation of multiple stable mutations in the genome of affected cells, perhaps resulting in neoplastic transformation when some critical number of transformation-related target genes become damaged. Thus, interactions of fundamental cellular processes play significant roles in sustaining cellular normality, and alteration of any of these homeostatic processes could entrain cells to the progressive genomic instability and phenotypic evolution characteristic of carcinogenesis. Here, we discuss possible molecular mechanisms governing DNA mutation and genomic instability in genetically normal cells that might account for the acquisition of genomic instability in somatic cells, leading to the development of neoplasia. These include (a) molecular alteration of genes encoding DNA repair enzymes, (b) molecular alteration of genes responsible for cell-cycle control mechanisms, and (c) direct molecular alteration of dominantly transforming cellular protooncogenes. We also discuss normal cellular processes involved with DNA replication and repair that can contribute to the mutational alteration of critical genes: e.g., slow repair of damaged DNA in specific genes, and the timing of normal gene-specific replication.

scholarly journals Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

2021 ◽  
Vol 9 ◽  
Author(s):  
Rafaela Fagundes ◽  
Leonardo K. Teixeira
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Genomic Instability ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Cyclin E ◽  
Replication Stress ◽  
Cyclin E1 ◽  
Cdk2 Complex

DNA replication must be precisely controlled in order to maintain genome stability. Transition through cell cycle phases is regulated by a family of Cyclin-Dependent Kinases (CDKs) in association with respective cyclin regulatory subunits. In normal cell cycles, E-type cyclins (Cyclin E1 and Cyclin E2, CCNE1 and CCNE2 genes) associate with CDK2 to promote G1/S transition. Cyclin E/CDK2 complex mostly controls cell cycle progression and DNA replication through phosphorylation of specific substrates. Oncogenic activation of Cyclin E/CDK2 complex impairs normal DNA replication, causing replication stress and DNA damage. As a consequence, Cyclin E/CDK2-induced replication stress leads to genomic instability and contributes to human carcinogenesis. In this review, we focus on the main functions of Cyclin E/CDK2 complex in normal DNA replication and the molecular mechanisms by which oncogenic activation of Cyclin E/CDK2 causes replication stress and genomic instability in human cancer.

scholarly journals Inherited Cardiac Arrhythmia Syndromes: Focus on Molecular Mechanisms Underlying TRPM4 Channelopathies

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Mohamed-Yassine Amarouch ◽  
Jaouad El Hilaly
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Large Family ◽  
Receptor Potential ◽  
Wide Distribution ◽  
Cellular Level ◽  
Loss Of Function ◽  
Clinical Phenotypes ◽  
Pathogenic Variants ◽  
Transient Receptor Potential Melastatin

The Transient Receptor Potential Melastatin 4 (TRPM4) is a transmembrane N-glycosylated ion channel that belongs to the large family of TRP proteins. It has an equal permeability to Na+ and K+ and is activated via an increase of the intracellular calcium concentration and membrane depolarization. Due to its wide distribution, TRPM4 dysfunction has been linked with several pathophysiological processes, including inherited cardiac arrhythmias. Many pathogenic variants of the TRPM4 gene have been identified in patients with different forms of cardiac disorders such as conduction defects, Brugada syndrome, and congenital long QT syndrome. At the cellular level, these variants induce either gain- or loss-of-function of TRPM4 channels for similar clinical phenotypes. However, the molecular mechanisms associating these functional alterations to the clinical phenotypes remain poorly understood. The main objective of this article is to review the major cardiac TRPM4 channelopathies and recent advances regarding their genetic background and the underlying molecular mechanisms.

scholarly journals The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1828
Author(s):  
Jared Kirui ◽  
Yara Abidine ◽  
Annasara Lenman ◽  
Koushikul Islam ◽  
Yong-Dae Gwon ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Molecular Mechanisms ◽  
Rna Virus ◽  
Ectopic Expression ◽  
Point Mutations ◽  
Cell Entry ◽  
Target Cells ◽  
Human Hepatoma Cells ◽  
Chikv Infection ◽  
Phosphatidylserine Receptor

Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells.

scholarly journals Genetics and Epigenetics of One-Carbon Metabolism Pathway in Autism Spectrum Disorder: A Sex-Specific Brain Epigenome?

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 782
Author(s):  
Veronica Tisato ◽  
Juliana A. Silva ◽  
Giovanna Longo ◽  
Ines Gallo ◽  
Ajay V. Singh ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Mthfr Gene ◽  
Spectrum Disorder ◽  
Fetal Life ◽  
Clinical Phenotypes ◽  
One Carbon Metabolism ◽  
Causes And Risk Factors ◽  
Individual Disease

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition affecting behavior and communication, presenting with extremely different clinical phenotypes and features. ASD etiology is composite and multifaceted with several causes and risk factors responsible for different individual disease pathophysiological processes and clinical phenotypes. From a genetic and epigenetic side, several candidate genes have been reported as potentially linked to ASD, which can be detected in about 10–25% of patients. Folate gene polymorphisms have been previously associated with other psychiatric and neurodegenerative diseases, mainly focused on gene variants in the DHFR gene (5q14.1; rs70991108, 19bp ins/del), MTHFR gene (1p36.22; rs1801133, C677T and rs1801131, A1298C), and CBS gene (21q22.3; rs876657421, 844ins68). Of note, their roles have been scarcely investigated from a sex/gender viewpoint, though ASD is characterized by a strong sex gap in onset-risk and progression. The aim of the present review is to point out the molecular mechanisms related to intracellular folate recycling affecting in turn remethylation and transsulfuration pathways having potential effects on ASD. Brain epigenome during fetal life necessarily reflects the sex-dependent different imprint of the genome-environment interactions which effects are difficult to decrypt. We here will focus on the DHFR, MTHFR and CBS gene-triad by dissecting their roles in a sex-oriented view, primarily to bring new perspectives in ASD epigenetics.

scholarly journals Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes

2021 ◽  
Author(s):  
Silvia Martin-Almedina ◽  
Kazim Ogmen ◽  
Ege Sackey ◽  
Dionysios Grigoriadis ◽  
Christina Karapouliou ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Fetal Hydrops ◽  
Clinical Phenotypes ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Disease Mechanisms ◽  
Novel Variants ◽  
Uncertain Significance ◽  
Clinical Phenotyping

Abstract Purpose Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. Methods Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. Results Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype–genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. Conclusion This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes.

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