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Aug 2024 DOI 10.14302/issn.2372-6601.jhor-24-5108
Zakaria Baniamer AnsamCorresponding author
Hereditary thrombotic diseases, or inherited bleeding disorders, are a group of genetic conditions that disrupt normal blood coagulation. These diseases result from mutations in genes encoding blood coagulation factors or other regulatory proteins, impairing the body's ability to regulate bleeding and clotting. The most common inherited clotting disorders are hemophilia A and B, which are associated with deficiencies in clotting factors VIII and IX, respectively. Von Willebrand disease (VWD) is another prevalent disorder characterized by a deficiency or dysfunction of the Von Willebrand factor, a protein essential for coagulation. Additionally, the Factor V Leiden mutation is linked to an increased risk of blood clots. The prevalence of inherited coagulation disorders varies significantly by region and subpopulation. It is estimated that 5,000 to 10,000 male newborns are born with hemophilia A or B each year. Von Willebrand disease is much more common, affecting about 1% of the global population. The Factor V Leiden mutation is found in significant percentages of certain populations, with 3–8% of Caucasians being carriers. While antithrombin deficiency is more common in some areas, the incidence of other inherited clotting disorders, such as Factor XI, protein C and S deficiencies, and VWD, varies widely worldwide. This study discusses the incidence of inherited clotting disorders and their impact on affected individuals and their families. It also covers new advancements in disease management, alternative therapy approaches, and contemporary diagnostic techniques, aiming to improve diagnoses, treatments, and outcomes for patients with hereditary clotting disorders.
Apr 2021 DOI 10.14302/issn.2692-1537.ijcv-21-3804
Isea RaúlCorresponding author
Fundación Instituto de Estudios Avanzados, Hoyo de la Puerta, Baruta, Venezuela.
An algorithm to determine the possible mutations that can occur in the S protein responsible of the Covid-19 in humans is designed. To do that, nine tridimensional sequences available in the Protein Data Bank similar to the initial strain sequenced in Wuhan (December 2019) are identified. The conditions driving this potential mutation are: (1) an accumulated number of mutations greater than (or equal to) 5 in each position; (2), a cumulative value of the different variations of Gibbs free energy less than -2.0 Kcal/mol; and (3), a squared fluctuation greater than 1.6 Å obtained according to calculations for normal mode analysis based on anisotropic network models (ANM) after averaging the first 20 vibration modes. The result is that 491 positions can mutate, while 424 positions did not provide any mutation. Finally, the results reveal that there are mutations that cannot be predicted, so more studies are needed to determine why they are present in the human population.
Jul 2019
K Jadhav ShivajiCorresponding author
Mapmygenome India Limited, Royal Demeure, Madhapur, Hyderabad -500081, India
Co-infection of HIV with Mycobacterium tuberculosis is a common event, particularly in developing countries. The emergence and spread of multidrug resistant tuberculosis (MDR-TB) is an increasing public problem in India. The drug-resistant M. tuberculosis strains are posing a significant challenge to TB control. This study used PCR to characterize mutations inside the rifampicin resistance-determining region (RRDR) of the rpoB gene in the rifampicin-resistant M. tuberculosis co-infected with HIV. All the rifampicin-resistant strains had missense mutations. Sequence analysis detected a single or multiple hotspot mutations in the RRDR region of the rpoB gene at codons 516, 512 and 531, in most strains. Furthermore, mutations also occur at codons 512, 514, 517 and 526. The results suggest that hotspot mutations in the rpoB gene are not the sole contributors to MDR-TB co-infected with HIV.
Oct 2016 DOI 10.14302/issn.2572-3030.jcgb-16-1276
Hayashi TakumaCorresponding author
Dept. of Obstetrics and Gynecology, Shinshu University School of Medicine, Japan,
Human uterine leiomyosarcoma (LMS) is neoplastic malignancy that typically arises in tissues of mesenchymal origin. The identification of novel molecular mechanism leading to human uterine LMS formation and the establishment of new therapies has been hampered by several critical points. We earlier reported that mice with a homozygous deficiency for proteasome beta subunit 9 (PSMB9)/b1i, an interferon (IFN)-g inducible factor, spontaneously develop uterine LMS. The use of research findings of the experiment with mouse model has been successful in increasing our knowledge and understanding of how alterations, in relevant oncogenic, tumour suppressive, and signaling pathways directly impact sarcomagenesis. The IFN-g pathway is important for control of tumour growth and invasion and, has been implicated in several malignant tumours. In this study, experiments with human tissues revealed a defective PSMB9/b1i expression in human uterine LMS that was traced to the IFN-g pathway and the specific effect of somatic mutations of Janus kinase (JAK1) molecule or promoter region on the transcriptional activation of PSMB9/b1i gene. Understanding the molecular mechanisms of human uterine LMS may lead to identification of new diagnostic candidates or therapeutic targets in human uterine LMS.
Sep 2024 DOI 10.14302/issn.2690-4721.ijcm-24-5195
Mutile Kavai SusanCorresponding author
The persistence of multidrug-resistant (MDR) Salmonella Typhi (S. Typhi) is a challenge especially in regions where typhoid is endemic. Surveillance of circulating genotypes of MDR S. Typhi is crucial in typhoid acute cases and carriers. This study aimed to investigate genotypic diversity of S. Typhi from symptomatic and asymptomatic children in endemic settings in Nairobi, Kenya. Symptomatic and asymptomatic individuals’ ≤ 16 years were recruited at four health facilities and tested for typhoid through stool cultures. The S. Typhi isolates were subjected to antibiotic susceptibility testing to investigate multidrug resistance. The MDR S. Typhi isolates’ DNA was extracted and illumina sequenced. Raw reads were de novo assembled and analyzed by pathogen-watch. From the 90 sequenced isolates, 60 (67%) were confirmed to be S. Typhi (sequence Type 1 and genotype 4.3.1). Out of the 60 S. Typhi strains; 39 (65%) had plasmids, from these 38 (97%) had IncHI1 plasmids alone. Out of the 60, 59 (98%) S. Typhi isolates had blaTEM-1D. Point mutations conferring reduced susceptibility to quinolones were detected in 42 (70%) of S. Typhi isolates, from these; 14 (33%) had gyrA S83Y , and 28 (67%) gyrB S464F genes, respectively. This study reports 4.3.1 (H58) as the most dominant S. Typhi genotype responsible for spread of MDR phenotypes carried on IncHI1 plasmids. Presence of MDR S. Typhi with resistance genes such as blaTEM-1Dand reduced susceptibility to ciprofloxacin especially among asymptomatic individuals, reiterates the need for use of typhoid conjugate vaccine among vulnerable children as a control and prevention measure against typhoid.
Mar 2024 DOI 10.14302/issn.2689-4602.jes-24-4956
Chadov B.F.Corresponding author
A new type of mutations-dominant lethals with a facultative manifestation -were discovered in D. melanogaster in 2000. These mutations were named conditional mutations. Under restrictive genetic conditions, the mutations manifest themselves as dominant lethals, whereas dominant lethality disappears under permissive conditions, displaying a set of other manifestations. The genes responsible for the emergence of conditional mutations were named ontogenes. The experiments with mutations in ontogenes have revealed the following processes: (1) genome editing in germline cells; (2) induction of high mutagenesis rates in germline cells of the mutants for ontogenes; (3) zygotic selection; (4) isolation of mutants; and (5) alterations in the lethality of mutants with time. The specific features in the manifestation of ontogenes together with the listed processes formed the background for construction of the model of speciation named the regeneration model. The event of speciation is represented as the regeneration of the working state of a genetic system disturbed by the emergence of a mutation in an ontogene. According to the model, it is ontogenes that are in charge of speciation and, eventually, the structure of living matter in the form of individual species. The significance of Mendelian protein-coding genes and Darwinian selection of the fittest according to these genes are doubtless but not paramount.
Feb 2024
Bandla ShaileCorresponding author
Background Junctional epidermolysis bullosa (JEB) is a type of Epidermolysis Bullosa, a group of genetic conditions that cause the skin to be very fragile and to blister easily. It is categorized into: the Herlitz type and the Non-Herlitz type. JEB is inherited in an autosomal recessive pattern. Most common genetic mutations associated are LAMB3, COL17A1, or LAMC2, and LAMA3 genes. Case presentation This study reports a consanguineous couple, carriers for pathogenic variant LAMB3 gene, with an affected child with a homozygous mutation in the LAMB3 gene causing Herlitz type of Junctional epidermolysis Bullosa/ Non-Herlitz type of junctional epidermolysis bullosa. Furthermore, prenatal diagnosis for the Gravida also showed the same pathogenic variant. Conclusion For autosomal recessive genetic conditions, it is advisable to perform a Trio whole-exome sequencing or next-generation sequencing to detect the genes associated with the disease. Depending on the type of variants involved prenatal diagnosis for the next pregnancy and treatment or management (if available) options can be offered/discussed.
Dec 2023 DOI 10.14302/issn.2324-7339.jcrhap-23-4634
Makura AlfredCorresponding author
Introduction Human Immunodeficiency Virus (HIV) remains a persistent global public health challenge. In 2020, approximately 37.9 million individuals were living with HIV globally, including 1.7 million children <15 years old, with a global HIV prevalence of 0.8% among adults. A larger portion of people living with HIV are found in low-and middle-income countries, and Sub-Saharan Africa (SSA) is home to about 68% of people living with HIV in the world. Strikingly, with increased uptakes in PMTCT, challenges in ART programs, and high viremia among children and adolescents in SSA, the success rate of ART might be quickly compromised, with possible HIVDR emergence, particularly after years of paediatric ART exposure. Therefore, monitoring ART response in children and adolescents in terms of HIVDR patterns and other socio-economic determinants of disease progression might help achieve better treatment outcomes at individual levels. At a programmatic level, this can guide further optimization of treatment options for SSA especially Zimbabwean rural where there is paucity of information on HIVDR prevalence in children and adolescents. Methods We enrolled 89 children and adolescents experiencing virologic failure from Chidamoyo Christian Hospital in Hurungwe. We managed to amplify all the 89 using nested PCR and 32.5% (29) had resistance to at least one ART drug and analysis was done using the 29 samples. Results Among the 89 participants with virologic failure,29 were resistant to at least one of their ART drugs. 39.2% of males and 23.07% of females had HIV-1 with resistance to at least one medication. Among 29 participants with HIVDR mutations, the prevalence of at least one HIVDR mutation to protease inhibitors (PIs), Nucleotide Reverse Transcriptase Inhibitors (NRTI), and Non-Nucleotide Reverse Transcriptase Inhibitors (NNRTI) were 6.47% ,46.76% and 46.76% respectively. Of the 29 participants who had HIVDR 19 (65.5%) had resistance to a drug they were currently taking and they needed to be switched to a better effective ART regimen Conclusion Use of HIVDR testing in guiding and monitoring development of HIVDR at the start of ART or at 1st failure can be very important in treatment options and patient management.
Sep 2023 DOI 10.14302/issn.2574-4496.jtc-23-4722
J. Conway PatrickCorresponding author
Background Patients with distant metastatic Medullary Thyroid Carcinoma (MTC) have an estimated 40% ten-year survival rate. Gain of function mutations in the REarranged during Transfection or RET gene in MTC can result in an aggressive phenotype resistant to traditional therapy. In this case report, we describe the treatment of an MTC patient with a unique RET kinase deletion mutation. Case presentation Since diagnosis, 21 years ago, this patient has had chronically elevated calcitonin levels (>40,000 pg/mL) that was unable to be controlled by conventual therapy and clinical trials. As result of uncontrolled MTC, metastatic disease was found in the spine, liver, and lungs. Circulating tumor DNA (ctDNA) analysis identified a RET 898-901Del mutation, reported as a variant of unknown significance. The treating physician identified that the deletion was in the activation loop of RET kinase and considered that the mutation was constitutively activating RET kinase. The patient was prescribed Pralsetinib, a small molecule inhibitor targeting the ATP binding site of RET. Pralsetinib treatment achieved a durable response and was able to significantly decrease serum calcitonin levels (<200 pg/mL) and tumor size. Conclusion This RET deletion mutation is a pathogenic mutation with comparable enzymatic activity to the more common RET M918T mutation. The case report highlights the versatility of structural biologic approaches to guide therapeutic decisions.
Aug 2023
Almabadi BayanCorresponding author
DADA2 (deficiency of adenosine deaminase type 2) is an autoinflammatory autosomal recessive disease resulting from biallelic loss of function mutations in ADA2 gene. Clinical presentation and age of onset vary widely even among related patients, and variability of symptoms and severity manifestations include bone marrow failure, autoinflammation, immunodeficiency and vasculitis. Here, we report a case of young male with adult onset DADA2, who presented with fever, lower limbs skin rash, joint pain, and anemia resembling systemic lupus erythematous (SLE). DADA2 has an extremely variable clinical phenotype. It was described into three categories: inflammatory/vascular, immune dysregulation, and hematologic. However, the data is scant in describing autoimmunity phenotype in DADA2 and further studies are required to investigate the clinical correlation and presence of autoantibodies. We recommend genetic testing in cases with lupus-like disease especially if there is consanguinity between parents and family history of vasculitis.
Jun 2022 DOI 10.14302/issn.2470-5020.jnrt-22-4217
O. Henderson JeffreyCorresponding author
Department of Science and Mathematics, Judson University, Elgin, IL 60123, USA
Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by mutations in the HEXA gene, which encodes the ɑ subunit of the enzyme β-hexosaminidase A. Lacking this key enzyme in GM2 ganglioside catabolism, individuals who are homozygous for HEXA mutations suffer from abnormal accumulation of GM2 ganglioside in brain and nerve cells, ultimately resulting in the progressive deterioration of the central nervous system. TSD is one of three disorders characterized by β-hexosaminidase deficiency; Sandhoff disease (SD) and the AB variant arise by mutations in the HEXB and GM2A genes respectively, which disrupt other points of GM2 ganglioside degradation. Characterized by developmental delay and stagnation, muscular weakness, coordination deficits, seizures, and eventual hearing and vision loss, these three disorders are clinically indistinguishable and occur in three forms defined by age of onset. While there is a much higher incidence of TSD in the Ashkenazi Jewish population, community carrier screening and counseling initiatives have reduced disease prevalence to about the equivalent of non-Jewish populations; however, such efforts have raised ethical concerns in the Jewish community that are increasingly relevant in light of scientific and medical advancements. Currently, treatments for TSD and its related disorders focus on symptom management, with gene therapies and the application of modified CRISPR-Cas-9 technology being explored.
Mar 2022 DOI 10.14302/issn.2572-3030.jcgb-22-4121
Pierre Diaga SARRCorresponding author
Laboratory of Clinical Cytology, Cytogenetics and Reproduction Biology, Aristide Le Dantec Hospital, Dakar-Senegal
Introduction Genomic mutations in TP53 gene in association with etiological risk factors have been associated with oral carcinogenesis. Herein, we screened for genomic variants of TP53 predisposing to oral cancers in Senegalese patients. Methodology 88 patients with confirmed diagnostic were recruited after informed consent. Blood samples were collected from each patient to perform DNA extraction, PCR amplification of all coding exons of TP53 followed by Sanger Sequencing of PCR products. Nucleotide sequences were analysed with Genalys software. 94 blood donors with no cancer diagnosis were also recruited as controls for association study between the most common variants identified in patients and predisposition to oral cancers. Results Sequence analysis showed that 52.27% of patients carry at least one mutation in TP53. Eleven genomic variants were identified, 7 variants already reported in databases and 4 new variants. The most recurrent variants in this study already reported as cancer-related variants were Pro72Arg (rs1042522; Arginine frequency estimated at 31.26%) and a 16 bp insertion in intron 3 (rs59758982; allelic frequency estimated at 26.25%). Haplotype analysis between these variants showed a strong linkage disequilibrium (D’ = 0.999, r2 = 0.153 and p-value < 0.05). However, association study did not find any significant association with susceptibility to oral cancer (p-value > 0.05). Conclusion Our study highlighted that despite the absence of association between the two most common cancer-related variants in Senegalese patients diagnosed with oral cancer, their strong LD suggested that they could be transmitted together in a common haplotype which may be implicated in oral carcinogenesis.
May 2021 DOI 10.14302/issn.2690-4721.ijcm-21-3835
Montes MilagrosaCorresponding author
Biodonostia Health Research Institute, Vaccine Preventable Diseases Group; Osakidetza Basque Health Service, Donostia University Hospital, Microbiology Department, 20014 San Sebastian, Spain.
Objective Real-time surveillance of SARS-CoV-2 variants of concern (VOC) is of essential public health importance. Rapid Antigen Detection Tests (RAgDT) have become first-line COVID-19 diagnostic methods in many regions, but this strategy can hamper the surveillance of the virus variants due to their decentralized performance. The aim of this study was to assess the usefulness of the remaining sample of a widely used RAgDT (Panbio) for the surveillance of the B.1.1.7 VOC using molecular methods. Methods Symptomatic individuals and asymptomatic close contacts of confirmed cases were routinely screened for SARS-CoV-2 infection using the RAgDT in Primary Health Care Centers. After performing the test, the extraction tubes containing the remaining biological material of RAgDT-positive cases were sent to the clinical microbiology laboratory where RT-PCRs detecting key mutations of the VOC were conducted. Results A valid result was obtained in 1770/1812 (97.7%) RAgDT-positive cases. Variant B.1.1.7 was detected in 34.7% of the patients, increasing from 0% to 87.7% between the weeks beginning January 4 and March 15, 2021. Conclusion The sample remaining after performing the Panbio RAgDT allowed to monitor the emergence and circulation of the B.1.1.7, greatly improving the population screened for the molecular study of SARS-CoV-2 variants.
May 2021 DOI 10.14302/issn.2689-4602.jes-21-3837
O. Henderson JeffreyCorresponding author
Department of Science and Mathematics, Judson University, Elgin, IL 60123, USA
The coronavirus infectious disease (20)19 (COVID-19) pandemic is caused by a newly identified virus (2019) SARS-CoV-2, a beta coronavirus that shares similarities with other human-infecting coronaviruses. Genomic analysis suggests that SARS-CoV-2 is closely related to SARS-CoV, a bat-related coronavirus, RaTG13, and to other pangolin-associated coronaviruses. The spike protein of coronaviruses are glycoproteins and are responsible for attaching the virus to the host cell and entering. Amino acid changes within the spike protein-encoding gene from SARS-CoV to SARS-CoV-2 enable SARS-CoV-2 to form a stable spike protein, to form a stable complex between the S protein and the receptor ACE2, to increase binding points between the S protein and ACE2, and to survive at higher temperatures. SARS-CoV-2 is zoonotic, with genomic analysis implicating bats as the original host and pangolins as the most likely intermediate host to infect humans. As SARS-CoV-2 infects humans, viral point mutations will continually occur and cause the emergence of new competitive SARS-CoV-2 strains. Two major strains include D614G and N501Y and have increased infectivity and transmission, further complicating the scope of the current COVID-19 pandemic. Vigilant monitoring of viral development and evolution is necessary for developing proper treatment methods and vaccine targets.
Jul 2020 DOI 10.14302/issn.2576-6694.jbbs-20-3450
M. Mahmoud MagdyCorresponding author
Faculty of Science, Ain Shams University, Cairo Egypt.
Background Hyperphenylalaninemia (HPA) combined with neurological signs due to impaired catecholamine, dopamine and serotonin synthesis. Symptoms may appears in first week of life but most seen in age of 4 months. Atypical PKU disease caused mainly by deficiency in 6-pyruvoyltetrahydropterin synthase (PTPS) involved in synthesis of BH4. Clinical symptoms may include poor sucking, impaired tone, ataxia, and seizures. The purpose of this study was to analyze the genotype-phenotype relation among BH4 deficient patients because of PTPS mutations in different state of Egypt. Methods Suspected PKU patients loaded with phenylalanine/Kuvan, and the level of phe and phe/tyrosine ratio determined using tandem mass spectrometry by dried blood spots. Blood samples of 13 unrelated Egyptian patients were collected for total RNA extraction, amplification of PTPS gene by PCR followed with sequencing by Sanger method and finally mutations were recorded for genetic analysis. Results The mean value of phe in 13 patients decreased after loaded of phenylalanine from 482.5μmol/L to 270.63 μmol/L as well as phe/tyrosine ratio was decreased from 13.4 to 6.36 after 24hour of treatment with Kuvan. Sanger sequencing of PTPS gene of those patient showed 21 SNPs and Indels mutations. The most repeated mutation is a novel 23 base pair homozygous deletion in 12/13; c.200C>T in four patients, a novel c.86A>T in two patients and three different mutations located once in three different patients (novel c.22C>T; novel c.273G>A and 405T>C) among patients. On amino acid predicted sequences 4 different types of mutations on protein level were presented, 1 deletion mutation in seven amino acid and 3 different missense mutations in addition to 2 silent mutations among 13 patients. Conclusion Patients were the first case of clinical diagnosis as hyperphenylalaninemia (HPA) undergoing genetic diagnosis for PTPS deficiency in Egypt. The sever HPA patients with severe nervous system damage mainly accompanied with deletion mutations and should pay more attention to the BH4 deficiency. While mild HPA is associated with base substitution mutations with mainly transition mutations (7/9; 78%). Next-generation sequencing technique can increase the mutation detection rate when the hereditary diseases are highly suspected in clinic.
Feb 2020 DOI 10.14302/issn.2690-4837.ijip-20-3176
Bajaj AnubhaCorresponding author
MD. (Pathology) Panjab University, Department of Histopathology, A.B. Diagnostics, A-1, Ring Road, Rajouri Garden, New Delhi, 110027, India.
Multiple endocrine neoplasia type 1 (MEN1) is a syndrome emerging from characteristic mutations of MEN1 gene with concurrently enunciated multiple endocrine and tumours and associated non-endocrine neoplasm. Previously designated as Werner’s syndrome, MEN1 syndrome denominates genomic mutation within chromosome 11q13 or a tumour suppressor gene with a distinctive protein product nomenclated as “menin”. MEN1 syndrome demonstrates an autosomal dominant pattern of disease inheritance where genomic mutations delineate a comprehensive (100%) disease penetrance. MEN1 gene was initially identified in 1997 upon chromosome 11q13. Although twelve genetic mutations were primarily identified, currently beyond eighteen hundred genomic mutations are scripted12. MEN1 syndrome is comprised of diverse combination of twenty or more endocrine and non-endocrine tumours exemplifying a classic triad of pituitary, parathyroid and pancreatic neoplasm. Diverse non endocrine tumours enunciated with MEN1 syndrome are denominated with meningioma, ependymoma or angiofibroma12. Endocrine tumours are discerned on account of excessive hormonal secretion engendered from various neoplasm or on account of neoplastic evolution. Approximately 10% instances can occur due to a de-novo genomic variant. Offspring of an individual with MEN1 syndrome quantifies a 50% possibility of inheriting the genomic variant. Cogent prenatal diagnosis can be determined in instances where specific genomic variant of a particular family is known. Physical, psychological and social restrictions are prevalent with MEN1 syndrome. Heterozygotes with MEN1 genetic variant are denominated as carriers and manifest a two- fold possible mortality12.
Oct 2019 DOI 10.14302/issn.2372-6601.jhor-19-2986
Riede IsoldeCorresponding author
Independent Cancer Research, Im Amann 7, Ueberlingen D-88662.
With the definition of four gene classes, all differences between tumor cells and normal cells can be explained. Proliferative mutations induce a shortcut, forcing the cell to divide. They allow replication without control, induce somatic pairing defects of chromosomes and genome instability. Intact Tumor Supressors or mutant Switch Functions can inhibit this process. Oncogene mutations optimize the growth of the cells.
Feb 2019 DOI 10.14302/issn.2689-4602.jes-18-2431
F Chadov BorisCorresponding author
Institute of Cytology and Genetics, Siberian Department of Russian Academy of Sciences, Novosibirsk 630090, Russian Federation.
The existing hypotheses on speciation rely on Mendelian genes and mutations in them. However, genome-wide sequencing demonstrates that the Mendelian genes account less than one-tenth of the entire genome DNA. This means that a greater part of the genome has not yet been subject to large-scale evolutionary consideration. This paper deals with the conditional mutations in drosophila, which are mutations of the genes belonging to a special category (ontogenes) controlling the program of individual development. The ontogenes presumably reside in the DNA of intergenic spaces and introns. Conditional mutations display a number of properties absent in the mutations of Mendelian genes. These specific properties allow three key problems in speciation to be solved: (1) the possibility of emergence of new traits as a result of sequential mutagenesis; (2) selection of mutants; and (3) establishment of isolation. We have shown that (1) the mutations in ontogenes are able to form new multigenic regulatory blocks that escape selection during their creation; (2) mutations in ontogenes allow for existence of constantly acting zygotic selection, which is by no means less important for speciation than Darwinian selection; and (3) owing to their conditionally lethal effect, the mutations in ontogenes are able to create biological isolation barrier. This gives the grounds for assuming that the emergence of mutations in ontogenes is a necessary condition for speciation.
Sep 2018 DOI 10.14302/issn.2641-9467.jgrc-18-2270
Li YuanCorresponding author
Department of Astronomy and Theoretical Physics
Rice, as one of the most important crops in the world, is facing an ever-accelerating challenge from climate change. Epigenetic modification with its substantially high epimutation rate and the possibility for some epigenetic variation to act as a heritable contributor to crop environmental adaptability may hold great potentials for rapid crop breeding. Epigenetic modification is controlled by epigenetic pathways, and mutations disturbing the epigenetic pathways may lead to significant epigenetic and/or genetic changes. This is especially true for rice, whose genome is rich in epigenetic modifications and transposable elements (TEs) that are generally epigenetically silenced. Here, in this paper, we first reviewed the pathways that establish, maintain and remove rice DNA methylation, which is the most well studied epigenetic marker, as well as the genes that are involved. We then discussed how TEs amplify the phenotypic impact of epigenetic changes that could be a result of epigenetic pathway disturbances. At last, we presented the enormous amount of rice genome data that are publically available, within which great genetic variation in the genes that are involved within the epigenetic pathways is embedded. This genetic variation awaits to be exploited for their potentials in generating a heritable source of variation for rapid environmental adaptation, which may hold tremendous importance for rice breeding in the face of climate change.
Aug 2018 DOI 10.14302/issn.2572-3030.jcgb-18-2183
F. Niculescu VladimirCorresponding author
Cell Biologist, Germany, Kirschenweg 1, 86420 Diedorf
This paper reviews the state of cancer research in the post-mutation era. It presents cancer as a highly complex disease viewed differently by scientists from various research fields. Histopathologists considered cancer as a disease of cell differentiation, cancer cell biologists overestimated the causal role of accumulated DNA mutations. More recently molecular biologists have focused on driver genes and driver mutations, regulatory gene networks and deregulation of the genomic balance between unicellular and multicellular gene sets (UG/MG balance). From a developmental biological standpoint, there is a clear analogy between the reproductive life cycles of cancer and protists. The key player of both analogous life cycles is the polyploid cyst, the atavistic cyst-like structure aCLS (PGCC). In the analogy to protists, we assume that the first aCLS initiating cancer originates from a mitoticly blocked cell (cell of origin of cancer, protoprecursor) that escapes death entering an atavistic reproductive process of polyploidisation and depolyploidisation; it forms the atavistic cyst-like structure aCLS and numerous daughter cells (microcells). The microcell progeny develops a multi-lined cell lineage containing stem cells as well as somatic and reproductive cells and clones. Subsequent aCLSs are formed sequentially by committed daughter cells or occasionally by stressed somatic cells. Accordingly, cancer initiation occurs by genomic changes leading to the amitotic cell state and reactivation of an atavistic life cycle. In humans, atavistic life cycles and hyperpolyploidisation (n >16) are mostly repressed by stable gene regulatory networks – but not in cancer. The permanent UG/MG gene conflict and robust ancient surveillance mechanisms trigger a cascade of molecular lesions leading to genomic heterogeneity and aberrant cancer cell states.
Apr 2018 DOI 10.14302/issn.2326-0793.jpgr-18-2004
Anwar PervezCorresponding author
Department of Biochemistry and molecular Biology, University of Gujrat Sialkot subcampus, Pakistan
Human proteome project was revolutionized about 40 years ago with purpose of summarizing whole proteomic data at one place. It was launched after human genome project to map and observe all proteins. The goal related proteomic study is to draft the entire human proteome in disease diagnosis by using bioinformatics tools. Pillars of human proteome project provide different databases related to proteins at transcriptional and translational level. Human proteome organization(HUPO) published biology disease HUPO whose aim is to measure protein and proteome by life and processes related to human diseases. Different human organ like plasma, liver, brain and diabetic base project are used to characterize human disease and health. Major data resources accumulated in databases like peptides Atlas, GPMDB and neXtProt for proteins. Matrices of human proteome project identify and characterize the protein products as Post translational modification (PTM), splice various isoforms from 20,300 proteins. Matrices related to different years make proteomes counterpart by magnify the research biomedical community with high output of instruments and specimen pre-analytical protocols. CALIPHO multidisciplinary group provides information about protein complexities, interactions, function and structure complexities after Uniport and Swissprot. Different bioinformatics tools are used for structural and functional annotations of protein, disease diagnosis and mutations due to protein. Extensive study of human proteome project has been proved helpful in disease treatment at translational and post- translational levels. In future, human proteome project along with bioinformatics will include protein profiling, biomarkers, Mass spectrophotometer technique and cross analysis of different proteome projects.
Aug 2017 DOI 10.14302/issn.2470-0436.jos-17-1721
C. Rodger DamienCorresponding author
USC Roski Eye Institute, Los Angeles, California
A 57-year-old Hispanic female presented with 3 days of blurry vision in the left eye. Eight years prior, she had a branch retinal artery occlusion in the right eye and a hematologic work-up revealed a 4G/4G polymorphism in plasminogen activator inhibitor-1. With the current episode, she was found to have bilateral branch retinal artery occlusions and mild vitritis in the left eye, simulating a toxoplasma infection. An infectious and inflammatory work up, however, was negative and the vitritis resolved after a short course of steroids. Plasminogen activator inhibitor-1 mutations may be associated with an increased risk of retinal vascular occlusions.
Aug 2017 DOI 10.14302/issn.2638-4469.japb-17-1563
Wanke DierkCorresponding author
Universität des Saarlandes, Molekulare Pflanzenbiologie, Campus A2.4, 66123 Saarbrücken, Germany
GAGA-binding proteins in plants are encoded by the BARLEY B-RECOMBINANT / BASIC PENTACYSTEINE (BBR/BPC) family, which can be spilt into several groups on the basis of sequence divergence. The proteins of the different groups share an evolutionary conserved BASIC PENTACYSTEINE (BPC) domain at their very C-terminus that is important for DNA binding. Hallmark of this domain are five Cysteines at defined positions and spacing, which are considered to form a zinc-finger like structure that is involved in GAGA-motif recognition. Here, we report the formation of stabile homodimers between Arabidopsis thaliana group I member BPC1 or between group II member BPC6 in SDS-PAGE. Serial mutations of the highly conserved five Cysteines in the BPC domain of Arabidopsis thaliana BPC1 were tested for their capacity to bind to GAGA-motifs by DPI-ELISA. Our results do not support the idea of a direct involvement of these residues in making physical contact with the DNA, e.g. by formation of a zinc-finger structure. Instead, the data implies an indispensable function for the five Cysteines in homodimerization and stabilization of the protein structure by disulfide bonds. Accordingly, protein folding and structure prediction suggests the formation of a scaffold for dimerization that is supported by three intermolecular and one intramolecular S-S bond. The high degree of conservation between the BPC domains from the different groups and from different species denotes that this role for the five Cysteines might be evolutionary retained.
Jul 2017 DOI 10.14302/issn.2577-2279.ijha-17-1538
Zou LipingCorresponding author
Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China.
Status thymico-lymphaticus had ever been explained as a cause of sudden death usually in children, but few cases were reported in adults. We sought to determine the relationship between thymic hypertrophy and sudden unexpected death in adult (SUDA), and associated macroscopic and microscopic findings. Adult post mortems from 1984 to 2014 were reviewed and 23 thymic hypertrophy patients without SUDA, 33 thymic hypertrophy patients with SUDA and 172 SUDAs without thymic hypertrophy entered. The data of thymus, lymph nodes, spleen, heart, aorta, and adrenal glands were collected for macroscopic and histological analysis. Ten antibodies were used and applied to 3 children and 46 adult thymus specimens. We found, as an independent factor, thymic hypertrophy increased significantly the risk of SUDA (6.9 folds) in both male and female. What’s more, SUDAs associated with thymic hypertrophy were quite younger (22.5 years) than those without it. A majority of patients with hypertrophic thymus had a variable number of accompanied anomalies described as the typical characteristics of status thymico-lymphaticus, but no macroscopic and microscopic findings related to SUDA in patients with thymic hypertrophy. Cytokeratins (CKs) showed distinctly different immunohistochemical expression patterns in individuals who had different death causes and disease background. Instead of a disease entity “status thymico-lymphaticus” is a systematic abnormality with thymic hypertrophy as a feature involving mainly immune and/or cardiovascular system, probably caused by gene mutations.
Jan 2017 DOI 10.14302/issn.2572-3030.jcgb-16-1307
Morales RafaelCorresponding author
Genetic Counselling Unit, Medical Oncology Department, Hospital La Mancha Centro, Av La Constitución, Nº 3, 13600, Alcázar de San Juan, Ciudad Real (Spain)
Interpreting variants of uncertain significance (VUS) for their effect on protein function, and therefore for the risk of developing cancer, has become a challenge in clinical practice for genetic counselling services. The present work combines structural bioinformatics and systems biology based mathematical modelling approaches with the aim of determining the pathogenicity of the mutation c.5434C->G (p.Pro1812Ala) in the BRCA1 gene (detected in a patient from a high risk family) and also to mechanistically understand the effect of this mutation in DNA damage response, a key process in cancer development. The results obtained showed that this mutation prevents the interaction of BRCA1 with key proteins of the cell cycle, subsequently impairing BRCA1-dependent induction of cell cycle arrest. The comparison of the molecular mechanisms associated with the native BRCA1 protein and the mutated variant function in DNA damage response showed that the latter undergoes a reduction in its ability to modulate pathways that are critical for DNA repair and cell cycle control. Therefore, this variant will not be able to exert its tumor suppressive action. Interestingly, these conclusions can be extrapolated to all mutations that, like c.5434C>G (p.Pro1812Ala) BRCA1, cause loss of BRCT domain activity.
Jan 2017 DOI 10.14302/issn.2575-7881.jdrr-16-1375
Góth LászlóCorresponding author
Department of Medical Laboratory and Diagnostic Imaging, University of Debrecen, Debrecen POBox 55, Hungary H-4012
We checked our simple screening technique for detection of the known polymorphism of rs769217, and the two acatalasemic mutations in exon 9 of the catalase gene. This fast and inexpensive method yielded better resolution than those of the standard SSCP. We suppose that the method detects the spontaneously formed single stranded DNAs.
Jun 2016 DOI 10.14302/issn.2470-5020.jnrt-16-993
Jurkat-Rott KarinCorresponding author
Division of Neurophysiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
Autosomal dominant inherited hypokalemic periodic paralysis (HypoPP) is caused by S4 voltage sensor mutations in skeletal muscle CaV1.1 calcium or NaV1.4 sodium channels. In the present study, a small German family with the known CaV1.1-R528G is described. The phenotype consists of short and infrequent episodes of limb weakness with ictal respiratory and cardiac involvement. There is incomplete penetrance in women, and acetazolamide is beneficial in two patients also taking daily potassium. Expression of the mutation in the GLT mouse muscle cell line revealed accelerated kinetics of inactivation by twofold, a left-shift of the steady-state inactivation curve by 13mV and a reduced recovery from fast inactivation by up to 39%. These changes suggest a stabilization of the inactivated state. Additional significant slowing of activation may support a second open state with differing ion selectivity or decreased activation of calcium-activated potassium channels and thereby contribute to weakness similar to other CaV1.1 mutations. Also, as documented for other HypoPP mutants, we found a hyperpolarization-induced inward guanidinium current of 22nS/nF which can be interpreted as an omega current along the voltage sensor gating pore that leads to a gain- of- function at potentials near the resting membrane potential. This finding can explain the long-lasting depolarizations that are known to lead to paralysis. The omega current is large enough so that a relatively mild hypokalemic trigger of 2.4mM already produces episodes of weakness in vivo.