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21 pages, 3707 KiB

Open AccessArticle

The Identification of a Novel Fucosidosis-Associated FUCA1 Mutation: A Case of a 5-Year-Old Polish Girl with Two Additional Rare Chromosomal Aberrations and Affected DNA Methylation Patterns

by Agnieszka Domin, Tomasz Zabek, Aleksandra Kwiatkowska, Tomasz Szmatola, Anna Deregowska, Anna Lewinska, Artur Mazur and Maciej Wnuk

Genes 2021, 12(1), 74; https://doi.org/10.3390/genes12010074 - 8 Jan 2021

Cited by 3 | Viewed by 2812

Abstract

Fucosidosis is a rare neurodegenerative autosomal recessive disorder, which manifests as progressive neurological and psychomotor deterioration, growth retardation, skin and skeletal abnormalities, intellectual disability and coarsening of facial features. It is caused by biallelic mutations in FUCA1 encoding the α-L-fucosidase enzyme, which in [...] Read more.

Fucosidosis is a rare neurodegenerative autosomal recessive disorder, which manifests as progressive neurological and psychomotor deterioration, growth retardation, skin and skeletal abnormalities, intellectual disability and coarsening of facial features. It is caused by biallelic mutations in FUCA1 encoding the α-L-fucosidase enzyme, which in turn is responsible for degradation of fucose-containing glycoproteins and glycolipids. FUCA1 mutations lead to severe reduction or even loss of α-L-fucosidase enzyme activity. This results in incomplete breakdown of fucose-containing compounds leading to their deposition in different tissues and, consequently, disease progression. To date, 36 pathogenic variants in FUCA1 associated with fucosidosis have been documented. Among these are three splice site variants. Here, we report a novel fucosidosis-related 9-base-pair deletion (NG_013346.1:g.10233_10241delACAGGTAAG) affecting the exon 3/intron 3 junction within a FUCA1 sequence. This novel pathogenic variant was identified in a five-year-old Polish girl with a well-defined pattern of fucosidosis symptoms. Since it is postulated that other genetic, nongenetic or environmental factors can also contribute to fucosidosis pathogenesis, we performed further analysis and found two rare de novo chromosomal aberrations in the girl’s genome involving a 15q11.1-11.2 microdeletion and an Xq22.2 gain. These abnormalities were associated with genome-wide changes in DNA methylation status in the epigenome of blood cells. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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18 pages, 3067 KiB

Open AccessArticle

46,XY,r(8)/45,XY,−8 Mosaicism as a Possible Mechanism of the Imprinted Birk-Barel Syndrome: A Case Study

by Anna A. Kashevarova, Tatyana V. Nikitina, Larisa I. Mikhailik, Elena O. Belyaeva, Stanislav A. Vasilyev, Mariya E. Lopatkina, Dmitry A. Fedotov, Elizaveta A. Fonova, Aleksei A. Zarubin, Aleksei A. Sivtsev, Nikolay A. Skryabin, Lyudmila P. Nazarenko and Igor N. Lebedev

Genes 2020, 11(12), 1473; https://doi.org/10.3390/genes11121473 - 9 Dec 2020

Cited by 3 | Viewed by 3602

Abstract

Ring chromosome 8 (r(8)) is one of the least frequent ring chromosomes. Usually, maternal chromosome 8 forms a ring, which can be lost from cells due to mitotic instability. The 8q24 region contains the imprinted KCNK9 gene, which is expressed from the maternal [...] Read more.

Ring chromosome 8 (r(8)) is one of the least frequent ring chromosomes. Usually, maternal chromosome 8 forms a ring, which can be lost from cells due to mitotic instability. The 8q24 region contains the imprinted KCNK9 gene, which is expressed from the maternal allele. Heterozygous KCNK9 mutations are associated with the imprinting disorder Birk-Barel syndrome. Here, we report a 2.5-year-old boy with developmental delay, microcephaly, dysmorphic features, diffuse muscle hypotonia, feeding problems, motor alalia and noncoarse neurogenic type of disturbance of muscle electrogenesis, partially overlapping with Birk-Barel syndrome phenotype. Cytogenetic analysis of lymphocytes revealed his karyotype to be 46,XY,r(8)(p23q24.3)[27]/45,XY,−8[3]. A de novo 7.9 Mb terminal 8p23.3p23.1 deletion, a 27.1 Mb 8p23.1p11.22 duplication, and a 4.4 Mb intact segment with a normal copy number located between them, as well as a 154-kb maternal LINGO2 gene deletion (9p21.2) with unknown clinical significance were identified by aCGH + SNP array. These aberrations were confirmed by real-time PCR. According to FISH analysis, the 8p23.1-p11.22 duplication was inverted. The ring chromosome originated from maternal chromosome 8. Targeted massive parallel sequencing did not reveal the KCNK9 mutations associated with Birk-Barel syndrome. Our data allow to assume that autosomal monosomy with inactive allele of imprinted gene arising from the loss of a ring chromosome in some somatic cells may be an etiological mechanism of mosaic imprinting disorders, presumably with less severe phenotype. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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11 pages, 832 KiB

Open AccessArticle

In Silico Model for Chemical-Induced Chromosomal Damages Elucidates Mode of Action and Irrelevant Positives

by Yurika Fujita, Osamu Morita and Hiroshi Honda

Genes 2020, 11(10), 1181; https://doi.org/10.3390/genes11101181 - 11 Oct 2020

Cited by 4 | Viewed by 2464

Abstract

In silico tools to predict genotoxicity have become important for high-throughput screening of chemical substances. However, current in silico tools to evaluate chromosomal damage do not discriminate in vitro-specific positives that can be followed by in vivo tests. Herein, we establish an in [...] Read more.

In silico tools to predict genotoxicity have become important for high-throughput screening of chemical substances. However, current in silico tools to evaluate chromosomal damage do not discriminate in vitro-specific positives that can be followed by in vivo tests. Herein, we establish an in silico model for chromosomal damages with the following approaches: (1) re-categorizing a previous data set into three groups (positives, negatives, and misleading positives) according to current reports that use weight-of-evidence approaches and expert judgments; (2) utilizing a generalized linear model (Elastic Net) that uses partial structures of chemicals (organic functional groups) as explanatory variables of the statistical model; and (3) interpreting mode of action in terms of chemical structures identified. The accuracy of our model was 85.6%, 80.3%, and 87.9% for positive, negative, and misleading positive predictions, respectively. Selected organic functional groups in the models for positive prediction were reported to induce genotoxicity via various modes of actions (e.g., DNA adduct formation), whereas those for misleading positives were not clearly related to genotoxicity (e.g., low pH, cytotoxicity induction). Therefore, the present model may contribute to high-throughput screening in material design or drug discovery to verify the relevance of estimated positives considering their mechanisms of action. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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18 pages, 2380 KiB

Open AccessArticle

Differential Regulation of Telomeric Complex by BCR-ABL1 Kinase in Human Cellular Models of Chronic Myeloid Leukemia—From Single Cell Analysis to Next-Generation Sequencing

by Anna Deregowska, Monika Pepek, Katarzyna Pruszczyk, Marcin M. Machnicki, Maciej Wnuk and Tomasz Stoklosa

Genes 2020, 11(10), 1145; https://doi.org/10.3390/genes11101145 - 29 Sep 2020

Cited by 13 | Viewed by 3370

Abstract

Telomeres are specialized nucleoprotein complexes, localized at the physical ends of chromosomes, that contribute to the maintenance of genome stability. One of the features of chronic myeloid leukemia (CML) cells is a reduction in telomere length which may result in increased genomic instability [...] Read more.

Telomeres are specialized nucleoprotein complexes, localized at the physical ends of chromosomes, that contribute to the maintenance of genome stability. One of the features of chronic myeloid leukemia (CML) cells is a reduction in telomere length which may result in increased genomic instability and progression of the disease. Aberrant telomere maintenance in CML is not fully understood and other mechanisms such as the alternative lengthening of telomeres (ALT) are involved. In this work, we employed five BCR-ABL1-positive cell lines, namely K562, KU-812, LAMA-84, MEG-A2, and MOLM-1, commonly used in the laboratories to study the link between mutation, copy number, and expression of telomere maintenance genes with the expression, copy number, and activity of BCR-ABL1. Our results demonstrated that the copy number and expression of BCR-ABL1 are crucial for telomere lengthening. We observed a correlation between BCR-ABL1 expression and telomere length as well as shelterins upregulation. Next-generation sequencing revealed pathogenic variants and copy number alterations in major tumor suppressors, such as TP53 and CDKN2A, but not in telomere-associated genes. Taken together, we showed that BCR-ABL1 kinase expression and activity play a crucial role in the maintenance of telomeres in CML cell lines. Our results may help to validate and properly interpret results obtained by many laboratories employing these in vitro models of CML. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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15 pages, 1108 KiB

Open AccessArticle

Mode and Tempo of Microsatellite Evolution across 300 Million Years of Insect Evolution

by Michelle Jonika, Johnathan Lo and Heath Blackmon

Genes 2020, 11(8), 945; https://doi.org/10.3390/genes11080945 - 16 Aug 2020

Cited by 8 | Viewed by 5438

Abstract

Microsatellites are short, repetitive DNA sequences that can rapidly expand and contract due to slippage during DNA replication. Despite their impacts on transcription, genome structure, and disease, relatively little is known about the evolutionary dynamics of these short sequences across long evolutionary periods. [...] Read more.

Microsatellites are short, repetitive DNA sequences that can rapidly expand and contract due to slippage during DNA replication. Despite their impacts on transcription, genome structure, and disease, relatively little is known about the evolutionary dynamics of these short sequences across long evolutionary periods. To address this gap in our knowledge, we performed comparative analyses of 304 available insect genomes. We investigated the impact of sequence assembly methods and assembly quality on the inference of microsatellite content, and we explored the influence of chromosome type and number on the tempo and mode of microsatellite evolution across one of the most speciose clades on the planet. Diploid chromosome number had no impact on the rate of microsatellite evolution or the amount of microsatellite content in genomes. We found that centromere type (holocentric or monocentric) is not associated with a difference in the amount of microsatellite content; however, in those species with monocentric chromosomes, microsatellite content tends to evolve faster than in species with holocentric chromosomes. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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Review

Jump to: Research

16 pages, 1789 KiB

Open AccessReview

Chromosomal Aberrations in Cattle

by Beáta Holečková, Viera Schwarzbacherová, Martina Galdíková, Simona Koleničová, Jana Halušková, Jana Staničová, Valéria Verebová and Annamária Jutková

Genes 2021, 12(9), 1330; https://doi.org/10.3390/genes12091330 - 27 Aug 2021

Cited by 14 | Viewed by 7791

Abstract

Chromosomal aberrations and their mechanisms have been studied for many years in livestock. In cattle, chromosomal abnormalities are often associated with serious reproduction-related problems, such as infertility of carriers and early mortality of embryos. In the present work, we review the mechanisms and [...] Read more.

Chromosomal aberrations and their mechanisms have been studied for many years in livestock. In cattle, chromosomal abnormalities are often associated with serious reproduction-related problems, such as infertility of carriers and early mortality of embryos. In the present work, we review the mechanisms and consequences of the most important bovine chromosomal aberrations: Robertsonian translocations and reciprocal translocations. We also discuss the application of bovine cell cultures in genotoxicity studies. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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35 pages, 20853 KiB

Open AccessReview

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

by Benilde García-de-Teresa, Alfredo Rodríguez and Sara Frias

Genes 2020, 11(12), 1528; https://doi.org/10.3390/genes11121528 - 21 Dec 2020

Cited by 48 | Viewed by 12836

Abstract

Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of [...] Read more.

Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired and accumulation of toxic DNA double strand breaks occurs. To repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, which may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA, and their segregation during cell division are the origin of subsequent aberrations such as translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, which results in tissue attrition, selection of malignant clones and cancer onset. Moreover, chromosomal instability and cell death are not exclusive of the somatic compartment, they also affect germinal cells, as evidenced by the infertility observed in patients with FA. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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24 pages, 648 KiB

Open AccessReview

A Tangle of Genomic Aberrations Drives Multiple Myeloma and Correlates with Clinical Aggressiveness of the Disease: A Comprehensive Review from a Biological Perspective to Clinical Trial Results

by Mariarosaria Sessa, Francesco Cavazzini, Maurizio Cavallari, Gian Matteo Rigolin and Antonio Cuneo

Genes 2020, 11(12), 1453; https://doi.org/10.3390/genes11121453 - 3 Dec 2020

Cited by 2 | Viewed by 2701

Abstract

Multiple myeloma (MM) is a genetically heterogeneous disease, in which the process of tumorigenesis begins and progresses through the appearance and accumulation of a tangle of genomic aberrations. Several are the mechanisms of DNA damage in MM, varying from single nucleotide substitutions to [...] Read more.

Multiple myeloma (MM) is a genetically heterogeneous disease, in which the process of tumorigenesis begins and progresses through the appearance and accumulation of a tangle of genomic aberrations. Several are the mechanisms of DNA damage in MM, varying from single nucleotide substitutions to complex genomic events. The timing of appearance of aberrations is well studied due to the natural history of the disease, that usually progress from pre-malignant to malignant phase. Different kinds of aberrations carry different prognostic significance and have been associated with drug resistance in some studies. Certain genetic events are well known to be associated with prognosis and are incorporated in risk evaluation in MM at diagnosis in the revised International Scoring System (R-ISS). The significance of some other aberrations needs to be further explained. Since now, few phase 3 randomized trials included analysis on patient’s outcomes according to genetic risk, and further studies are needed to obtain useful data to stratify the choice of initial and subsequent treatment in MM. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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17 pages, 1458 KiB

Open AccessReview

Consequences of 22q11.2 Microdeletion on the Genome, Individual and Population Levels

by Małgorzata Karbarz

Genes 2020, 11(9), 977; https://doi.org/10.3390/genes11090977 - 22 Aug 2020

Cited by 9 | Viewed by 13633

Abstract

Chromosomal 22q11.2 deletion syndrome (22q11.2DS) (ORPHA: 567) caused by microdeletion in chromosome 22 is the most common chromosomal microdeletion disorder in humans. Despite the same change on the genome level, like in the case of monozygotic twins, phenotypes are expressed differently in 22q11.2 [...] Read more.

Chromosomal 22q11.2 deletion syndrome (22q11.2DS) (ORPHA: 567) caused by microdeletion in chromosome 22 is the most common chromosomal microdeletion disorder in humans. Despite the same change on the genome level, like in the case of monozygotic twins, phenotypes are expressed differently in 22q11.2 deletion individuals. The rest of the genome, as well as epigenome and environmental factors, are not without influence on the variability of phenotypes. The penetrance seems to be more genotype specific than deleted locus specific. The transcript levels of deleted genes are not usually reduced by 50% as assumed due to haploinsufficiency. 22q11.2DS is often an undiagnosed condition, as each patient may have a different set out of 180 possible clinical manifestations. Diverse dysmorphic traits are present in patients from different ethnicities, which makes diagnosis even more difficult. 22q11.2 deletion syndrome serves as an example of a genetic syndrome that is not easy to manage at all stages: diagnosis, consulting and dealing with. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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27 pages, 3639 KiB

Open AccessReview

Consequence of Paradigm Shift with Repeat Landscapes in Reptiles: Powerful Facilitators of Chromosomal Rearrangements for Diversity and Evolution

by Syed Farhan Ahmad, Worapong Singchat, Maryam Jehangir, Thitipong Panthum and Kornsorn Srikulnath

Genes 2020, 11(7), 827; https://doi.org/10.3390/genes11070827 - 21 Jul 2020

Cited by 29 | Viewed by 5685

Abstract

Reptiles are notable for the extensive genomic diversity and species richness among amniote classes, but there is nevertheless a need for detailed genome-scale studies. Although the monophyletic amniotes have recently been a focus of attention through an increasing number of genome sequencing projects, [...] Read more.

Reptiles are notable for the extensive genomic diversity and species richness among amniote classes, but there is nevertheless a need for detailed genome-scale studies. Although the monophyletic amniotes have recently been a focus of attention through an increasing number of genome sequencing projects, the abundant repetitive portion of the genome, termed the “repeatome”, remains poorly understood across different lineages. Consisting predominantly of transposable elements or mobile and satellite sequences, these repeat elements are considered crucial in causing chromosomal rearrangements that lead to genomic diversity and evolution. Here, we propose major repeat landscapes in representative reptilian species, highlighting their evolutionary dynamics and role in mediating chromosomal rearrangements. Distinct karyotype variability, which is typically a conspicuous feature of reptile genomes, is discussed, with a particular focus on rearrangements correlated with evolutionary reorganization of micro- and macrochromosomes and sex chromosomes. The exceptional karyotype variation and extreme genomic diversity of reptiles are used to test several hypotheses concerning genomic structure, function, and evolution. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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16 pages, 274 KiB

Open AccessReview

A Dual Face of APE1 in the Maintenance of Genetic Stability in Monocytes: An Overview of the Current Status and Future Perspectives

by Gabriela Betlej, Ewelina Bator, Antoni Pyrkosz and Aleksandra Kwiatkowska

Genes 2020, 11(6), 643; https://doi.org/10.3390/genes11060643 - 11 Jun 2020

Cited by 3 | Viewed by 2633

Abstract

Monocytes, which play a crucial role in the immune system, are characterized by an enormous sensitivity to oxidative stress. As they lack four key proteins responsible for DNA damage response (DDR) pathways, they are especially prone to reactive oxygen species (ROS) exposure leading [...] Read more.

Monocytes, which play a crucial role in the immune system, are characterized by an enormous sensitivity to oxidative stress. As they lack four key proteins responsible for DNA damage response (DDR) pathways, they are especially prone to reactive oxygen species (ROS) exposure leading to oxidative DNA lesions and, consequently, ROS-driven apoptosis. Although such a phenomenon is of important biological significance in the regulation of monocyte/macrophage/dendritic cells’ balance, it also a challenge for monocytic mechanisms that have to provide and maintain genetic stability of its own DNA. Interestingly, apurinic/apyrimidinic endonuclease 1 (APE1), which is one of the key proteins in two DDR mechanisms, base excision repair (BER) and non-homologous end joining (NHEJ) pathways, operates in monocytic cells, although both BER and NHEJ are impaired in these cells. Thus, on the one hand, APE1 endonucleolytic activity leads to enhanced levels of both single- and double-strand DNA breaks (SSDs and DSBs, respectively) in monocytic DNA that remain unrepaired because of the impaired BER and NHEJ. On the other hand, there is some experimental evidence suggesting that APE1 is a crucial player in monocytic genome maintenance and stability through different molecular mechanisms, including induction of cytoprotective and antioxidant genes. Here, the dual face of APE1 is discussed. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

15 pages, 1406 KiB

Open AccessReview

The Oncogenic Potential of the Centromeric Border Protein FAM84B of the 8q24.21 Gene Desert

by Yan Gu, Xiaozeng Lin, Anil Kapoor, Mathilda Jing Chow, Yanzhi Jiang, Kuncheng Zhao and Damu Tang

Genes 2020, 11(3), 312; https://doi.org/10.3390/genes11030312 - 15 Mar 2020

Cited by 13 | Viewed by 4059

Abstract

FAM84B is a risk gene in breast and prostate cancers. Its upregulation is associated with poor prognosis of prostate cancer, breast cancer, and esophageal squamous cell carcinoma. FAM84B facilitates cancer cell proliferation and invasion in vitro, and xenograft growth in vivo. The FAM84B [...] Read more.

FAM84B is a risk gene in breast and prostate cancers. Its upregulation is associated with poor prognosis of prostate cancer, breast cancer, and esophageal squamous cell carcinoma. FAM84B facilitates cancer cell proliferation and invasion in vitro, and xenograft growth in vivo. The FAM84B and Myc genes border a 1.2 Mb gene desert at 8q24.21. Co-amplification of both occurs in 20 cancer types. Mice deficient of a 430 Kb fragment within the 1.2 Mb gene desert have downregulated FAM84B and Myc expressions concurrent with reduced breast cancer growth. Intriguingly, Myc works in partnership with other oncogenes, including Ras. FAM84B shares similarities with the H-Ras-like suppressor (HRASLS) family over their typical LRAT (lecithin:retinal acyltransferase) domain. This domain contains a catalytic triad, H23, H35, and C113, which constitutes the phospholipase A_1/2 and O-acyltransferase activities of HRASLS1-5. These enzymatic activities underlie their suppression of Ras. FAM84B conserves H23 and H35 but not C113 with both histidine residues residing within a highly conserved motif that FAM84B shares with HRASLS1-5. Deletion of this motif abolishes FAM84B oncogenic activities. These properties suggest a collaboration of FAM84B with Myc, consistent with the role of the gene desert in strengthening Myc functions. Here, we will discuss recent research on FAM84B-derived oncogenic potential. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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