scholarly journals NTPDase5/PCPH as a New Target in Highly Aggressive Tumors: A Systematic Review

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Paula Andreghetto Bracco ◽  
Ana Paula Santin Bertoni ◽  
Márcia Rosângela Wink
Keyword(s):  
Cancer Progression ◽  
Stop Codon ◽  
Active Form ◽  
Premature Stop Codon ◽  
Diagnostic Tools ◽  
Therapy Targets ◽  
Base Pair Deletion ◽  
Wide Range ◽  
Resistance To Stress ◽  
Single Base Pair

The protooncogenePCPHwas recently identified as being the ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5). This protooncogene is converted into an oncogene by a single base pair deletion, resulting in frame change and producing a premature stop codon, leading to a mutated protein (mt-PCPH) with only 27 kDa, which is much smaller than the original 47 kDa protein. Overexpression of the PCPH as well as the mutated PCPH increases the cellular resistance to stress and apoptosis. This is intriguing considering that the active form, that is, the oncogene, is the mutated PCPH. Several studies analyzed the expression of NTPDase5/mt-PCPH in a wide range of tumor cells and evaluated its role and mechanisms in cancer and other pathogenic processes. The main point of this review is to integrate the findings and proposed theories about the role played by NTPDase5/mt-PCPH in cancer progression, considering that these proteins have been suggested as potential early diagnostic tools and therapy targets.

scholarly journals A rare large duplication of MLH1 identified in Lynch syndrome

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhishek Kumar ◽  
Nagarajan Paramasivam ◽  
Obul Reddy Bandapalli ◽  
Matthias Schlesner ◽  
Tianhui Chen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lynch Syndrome ◽  
Splice Site ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Splice Donor Site ◽  
Laboratory Diagnostics ◽  
Mmr Genes ◽  
Base Pair Deletion ◽  
Splice Site Variant

Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.

scholarly journals Identification of the genomic mutation in Epha4rb-2J/rb-2J mice

Genome ◽  
2016 ◽  
Vol 59 (7) ◽  
pp. 439-448 ◽  
Author(s):  
Siti W. Mohd-Zin ◽  
Nor-Linda Abdullah ◽  
Aminah Abdullah ◽  
Nicholas D.E. Greene ◽  
Pike-See Cheah ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Tyrosine Kinases ◽  
Stop Codon ◽  
Cell Signalling ◽  
Experimental Studies ◽  
Premature Stop Codon ◽  
Mouse Mutant ◽  
Functional Studies ◽  
Base Pair Deletion ◽  
Numerous Cell

The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4rb-2J/rb-2J, is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or “hopping gait” phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4rb-2J corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4rb-2J allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein–protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.

scholarly journals Genetic variability of spelt factor gene in Triticum and Aegilops species

2020 ◽  
Vol 20 (S1) ◽  
Author(s):  
Valeriya Vavilova ◽  
Irina Konopatskaia ◽  
Alexandr Blinov ◽  
Elena Ya. Kondratenko ◽  
Yuliya V. Kruchinina ◽  
...  
Keyword(s):  
Phylogenetic Relationships ◽  
Chinese Spring ◽  
Stop Codon ◽  
Aegilops Tauschii ◽  
Premature Stop Codon ◽  
Gene Sequences ◽  
D Genome ◽  
Factor Gene ◽  
Spike Shape ◽  
Wide Range

Abstract Background Threshability, rachis fragility and spike shape are critical traits for the domestication and evolution of wheat, determining the crop yield and efficiency of the harvest. Spelt factor gene Q controls a wide range of domestication-related traits in polyploid wheats, including those mentioned above. The main goal of the present study was to characterise the Q gene for uninvestigated accessions of wheats, including four endemics, and Aegilops accessions, and to analyze the species evolution based on differences in Q gene sequences. Results We have studied the spike morphology for 15 accessions of wheat species, including four endemics, namely Triticum macha, T. tibetanum, T. aestivum ssp. petropavlovskyi and T. spelta ssp. yunnanense, and 24 Aegilops accessions, which are donors of B and D genomes for polyploid wheat. The Q-5A, q-5D and q-5S genes were investigated, and a novel allele of the Q-5A gene was found in accessions of T. tibetanum (KU510 and KU515). This allele was similar to the Q allele of T. aestivum cv. Chinese Spring but had an insertion 161 bp in length within exon 5. This insertion led to a frameshift and premature stop codon formation. Thus, the T. tibetanum have spelt spikes, which is probably determined by the gene Tg, rather than Q. We determined the variability within the q-5D genes among hexaploid wheat and their D genome donor Aegilops tauschii. Moreover, we studied the accessions C21–5129, KU-2074, and K-1100 of Ae. tauschii ssp. strangulata, which could be involved in the origin of hexaploid wheats. Conclusions The variability and phylogenetic relationships of the Q gene sequences studied allowed us to clarify the relationships between species of the genus Triticum and to predict the donor of the D genome among the Ae. tauschii accessions. Ae. tauschii ssp. strangulata accessions C21–5129, KU-2074 and K-1100 are the most interesting among the analysed accessions, since their partial sequence of q-5D is identical to the q-5D of T. aestivum cv. Chinese Spring. This result indicates that the donor is Ae. tauschii ssp. strangulata but not Ae. tauschii ssp. tauschii. Our analysis allowed us to clarify the phylogenetic relationships in the genus Triticum.

scholarly journals Molecular structure of soybean E-genes and their functional mutations

2020 ◽  
pp. 3-13
Author(s):  
O. Okhrymovych ◽  
◽  
S. Chebotar ◽  
G. Chebotar ◽  
D. Zharikova ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Genetic Network ◽  
Structural Features ◽  
Loss Of Function ◽  
Nucleotide Substitutions ◽  
Early Maturity ◽  
E Gene ◽  
Wide Range

In this review, we discuss features of the molecular structure of known E-loci (early maturity) and their involvement in signaling to plant flowering, depending on the sensitivity of soybean genotypes to the photoperiod. These loci contribute to the adaptation of plants to a wide range of natural conditions due to mutations in genes and QTL that control flowering time. At the molecular level, E-genes are significantly different in structural features, origin and function. The lenghth of the identified genes range from one exon to 525 bp encoding the transcription factor (E1), up to 14 exons and about 20 kb for the GmGIa gene (E2). Among the functional mutations that in most cases lead to partial or complete loss of function, there are single-nucleotide substitutions or deletions, insertions of transposon-like sequences that can lead to amino acid substitutions in the protein, shift of the reading frame, appearance of the premature stop-codon. E-gene products are receptors of signals coming from the environment and they participate in signaling pathways that control the photoperiod. The overall impact and interactions between E-genes have not been fully studied yet, the molecular structure was investigated only for E1-E4, for which a genetic network of interactions was proposed, while at the same time five loci (E6-E9 and E11) were only mapped on soybean chromosomes, and the existence of a separate E5 locus has not yet been established. In eight of the 11 E-loci, the dominant allele causes late flowering. Also there is a pleiotropic effect of E-gene alleles on yield, plant height, stress resistance, and response to low temperatures. Knowledge of the allelic state of only some of the 11 genes is not sufficient. A comprehensive understanding of the functioning of the photoperiodic genetic response network is needed. E-genes are genetic determinants that can be used during selection and creation of new varieties with programmed rates of development.

scholarly journals Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 988-992 ◽  
Author(s):  
Stephen T. Oh ◽  
Erin F. Simonds ◽  
Carol Jones ◽  
Matthew B. Hale ◽  
Yury Goltsev ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Stop Codon ◽  
Myeloproliferative Neoplasms ◽  
Premature Stop Codon ◽  
Adaptor Protein ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Negative Feedback Regulation ◽  
Base Pair Deletion ◽  
Stat Signaling

Abstract Dysregulated Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling due to activation of tyrosine kinases is a common feature of myeloid malignancies. Here we report the first human disease-related mutations in the adaptor protein LNK, a negative regulator of JAK-STAT signaling, in 2 patients with JAK2 V617F–negative myeloproliferative neoplasms (MPNs). One patient exhibited a 5 base-pair deletion and missense mutation leading to a premature stop codon and loss of the pleckstrin homology (PH) and Src homology 2 (SH2) domains. A second patient had a missense mutation (E208Q) in the PH domain. BaF3-MPL cells transduced with these LNK mutants displayed augmented and sustained thrombopoietin-dependent growth and signaling. Primary samples from MPN patients bearing LNK mutations exhibited aberrant JAK-STAT activation, and cytokine-responsive CD34+ early progenitors were abnormally abundant in both patients. These findings indicate that JAK-STAT activation due to loss of LNK negative feedback regulation is a novel mechanism of MPN pathogenesis.

A new ferrochelatase mutation combined with low expression alleles in a Japanese patient with erythropoietic protoporphyria

2002 ◽  
Vol 102 (5) ◽  
pp. 501-506 ◽  
Author(s):  
Yumiko YASUI ◽  
Shikibu MURANAKA ◽  
Tsuyoshi TAHARA ◽  
Ryo SHIMIZU ◽  
Sonoko WATANABE ◽  
...  
Keyword(s):  
Base Pair ◽  
Japanese Patient ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Amino Acid Position ◽  
Molecular Defect ◽  
Wild Type ◽  
Erythropoietic Protoporphyria ◽  
Base Pair Deletion ◽  
Low Expression

We investigated the molecular defect of the ferrochelatase gene in a Japanese patient with erythropoietic protoporphyria (EPP), and identified a novel 16 base pair (574-589) deletion within exon 5. This deletion resulted in a frame-shift mutation and created a premature stop codon at amino acid position 198. The same molecular defect was also identified in his mother and a brother who had symptomatic EPP, but not in his father who was asymptomatic. The subjects with EPP were homozygous for the low expression haplotype, while his father was heterozygous for this haplotype. These results indicate that the combination of a 16 base pair deletion and low expression of the wild-type allelic variant is responsible for EPP in this pedigree.

scholarly journals Resistance to Infection by Subgroups B, D, and E Avian Sarcoma and Leukosis Viruses Is Explained by a Premature Stop Codon within a Resistance Allele of the tvb Receptor Gene

2002 ◽  
Vol 76 (15) ◽  
pp. 7918-7921 ◽  
Author(s):  
Sara Klucking ◽  
Heather B. Adkins ◽  
John A. T. Young
Keyword(s):  
Stop Codon ◽  
Receptor Gene ◽  
Premature Stop Codon ◽  
Resistance Allele ◽  
Truncated Protein ◽  
Single Base ◽  
Single Base Pair ◽  
Resistance To Infection ◽  
Avian Sarcoma

ABSTRACT Here we present the first molecular characterization of the defect associated with an avian sarcoma and leukosis virus (ASLV) receptor resistance allele, tvb r. We show that resistance to infection by subgroups B, D, and E ASLV is explained by the presence of a single base pair mutation that distinguishes this allele from tvb s1, an allele which encodes a receptor for all three viral subgroups. This mutation generates an in-frame stop codon that is predicted to lead to the production of a severely truncated protein.

Novel Identification of a Four-base-pair Deletion Mutation in PITX2 in a Rieger Syndrome Family

2003 ◽  
Vol 82 (12) ◽  
pp. 1008-1012 ◽  
Author(s):  
Y. Wang ◽  
H. Zhao ◽  
X. Zhang ◽  
H. Feng
Keyword(s):  
Base Pair ◽  
Stop Codon ◽  
Critical Role ◽  
Premature Stop Codon ◽  
Chinese Family ◽  
Loss Of Function ◽  
Rieger Syndrome ◽  
Mutational Screening ◽  
Base Pair Deletion ◽  
Pitx2 Gene

Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis.

scholarly journals Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5555
Author(s):  
Prithi Raguraman ◽  
Akilandeswari Ashwini Balachandran ◽  
Suxiang Chen ◽  
Sarah D. Diermeier ◽  
Rakesh N. Veedu
Keyword(s):  
Cancer Progression ◽  
Messenger Rna ◽  
Splice Variants ◽  
Stop Codon ◽  
Mrna Level ◽  
Premature Stop Codon ◽  
Exon Skipping ◽  
Protein Isoforms ◽  
Delivery Strategies ◽  
And Function

Splicing is an essential process wherein precursor messenger RNA (pre-mRNA) is reshaped into mature mRNA. In alternative splicing, exons of any pre-mRNA get rearranged to form mRNA variants and subsequently protein isoforms, which are distinct both by structure and function. On the other hand, aberrant splicing is the cause of many disorders, including cancer. In the past few decades, developments in the understanding of the underlying biological basis for cancer progression and therapeutic resistance have identified many oncogenes as well as carcinogenic splice variants of essential genes. These transcripts are involved in various cellular processes, such as apoptosis, cell signaling and proliferation. Strategies to inhibit these carcinogenic isoforms at the mRNA level are promising. Antisense oligonucleotides (AOs) have been developed to inhibit the production of alternatively spliced carcinogenic isoforms through splice modulation or mRNA degradation. AOs can also be used to induce splice switching, where the expression of an oncogenic protein can be inhibited by the induction of a premature stop codon. In general, AOs are modified chemically to increase their stability and binding affinity. One of the major concerns with AOs is efficient delivery. Strategies for the delivery of AOs are constantly being evolved to facilitate the entry of AOs into cells. In this review, the different chemical modifications employed and delivery strategies applied are discussed. In addition to that various AOs in clinical trials and their efficacy are discussed herein with a focus on six distinct studies that use AO-mediated exon skipping as a therapeutic strategy to combat cancer.

Sign in / Sign up

Export Citation Format

Share Document