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Articles Related to Mutation

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the P. Y181H Variant and a Literature Review

Deficiency of proprotein convertase 1/3 (PC1/3), is a known cause of monogenic obesity. This protein is encoded by the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene and PC1/3 deficiency patients carry either homozygous or compound heterozygous PCSK1 variants. Previously, it was also reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, resulted in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5: c.541T>C) variant, which was shown to affect proper PC1/3 maturation but not its enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolescents with obesity, and 486 healthy and lean individuals, recruited from Belgian hospitals. We identified three obese (0.62%) and four lean (0.82%) p.Y181H carriers (p = 0.506), indicating no association of the variant with obesity. Next, haplotype analysis was performed in 13 p.Y181H carriers, 20 non-carriers (10 with obesity and 10 lean) and two p.Y181H families. All heterozygous carriers were found to share the same haplotype (p < 0.001). Together with the higher frequency of this variant in Central European populations and the notably high frequency in the Belgian population, this indicates a possible founder effect for the p.Y181H variant. State-of-the-art literature concerning the role of rare heterozygous PCSK1 variants similarly implies them to be rarely associated to monogenic obesity, as first-degree carrier relatives of patients with PC1/3 deficiency are mostly not reported to be obese. Furthermore, recent meta-analyses have only indicated a robust association for scarce disruptive heterozygous PCSK1 variants with obesity, while clinical significance is less or sometimes lacking for most nonsynonymous PCSK1 variants.
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Prevalence of Minority Mutations That Confer Multi-Drug Resistance Among Patients Failing a Nucleoside Reverse Transcriptase Inhibitor Based Regimen in Uganda

Background:The extensive use of antiretroviral therapy has favored the emergence of multiple patterns of drug resistance mutations. These mutations evolve over time and are only detected by the conventional Sanger sequencing technology when they exceed 20% at which time there may be cross resistance. Unfortunately, the controversy surrounding the significance of these minority drug resistance mutations is still overwhelming. Methods: Samples were obtained from patients who were failing on an NRTI based regimen between 2010 and 2019. For the subtype A and D analysis, 1000 patient samples were analyzed while the subtype C sub-analysis was comprised of 363 samples. Sanger based sequencing was performed as part of the standard of care. A subset of these samples was further analyzed using the Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cut off to determine the prevalence of minority multi-drug resistant variants. Results: Although Thymidine analog mutations (TAMs) were prevalent in all subtypes, our analyses showed that these mutations occurred in significantly less proportions among subtype C infections when compared with the subtype A and D counterparts. On the other hand, the Q151M mutation complex was significantly more predominant among patients harboring subtype C variants. Analysis using NGS revealed that minority drug resistant mutations that confer multi-drug resistance (MDR) were present even in patients who exhibited a susceptible genotype based on the Sanger sequencing technique. Conclusion: Although HIV-1 MDR variants occur in all subtypes, their predominance is subtype specific with TAMs being significantly more predominant among subtype A and D while the Q151M complex more predominant among patients harboring subtype C viruses. Even in patients with a fully susceptible genotype based on Sanger technology, minority variants are present and their evolution to full blown MDR occurs over time such that if their early detection is missed, cross resistance is inevitable.
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A Novel Coenzyme Q8A Mutation in a Case with Juvenile-Onset Coenzyme Q10D4: Case Report and Literature Review

Primary coenzyme Q10 deficiency-4 (CoQ10D4) is an autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Molecular pathology responsible for clinical findings is mitochondrial respiratory chain dysfunction. The main clinical manifestation involves early-onset exercise intolerance, progressive cerebellar ataxia and movement disorders. Some affected individuals develop seizures and have mild mental impairment, indicating variable severity.
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Correlation of Hemostatic Parameters with Poly (ADP-ribose) Polymerase-1 (PARP-1) Polymorphisms, Mutations, Laboratory, and Clinical Characteristics in 114 Patients with Philadelphia-Negative Myeloproliferative Neoplasms

Patients with Philadelphia-negative myeloproliferative neoplasms (PN-MPN) are at a higher risk for venous thrombosis. Thromboelastometry may prove efficient to evaluate the patient’s thrombotic risk. In this study, based on data from 114 patients with PN-MPN from a single center in Greece, hemostatic profile was assessed with routine coagulation tests, Rotational Thromboelastometry (ROTEM® ), and Platelet Function Analyzer (PFA)-100 and correlated with clinical, laboratory, treatment characteristics, gene mutations and polymorphisms of poly (ADP-ribose) polymerase-1 (PARP-1)
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Genetic Variation of SARS-CoV-2 Circulating Worldwide and its Association for Altering Disease Fatality

The emergence of SARS-CoV-2 has resulted in > 36,361,054 infections and > 1,056,186 deaths worldwide. Using publicly available genome sequences of patient samples from different geographical regions, a study has been conducted to co-relate mutational frequency with disease transmission and fatality rate.
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A Novel Hemizygous Mutation of HCFC1 Causes X-Linked Recessive Gene Inherited Developmental Delay in a Chinese Family

Developmental delay (DD) / intellectual disability (ID) is considered one of the most genetically heterogeneous human diseases. Herein, we described a Chinese boy affected by DD/ID with 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) and 3-hydroxy3-methylglutaric aciduria (3-HMG), which associated with a novel missense hemizygous mutation, c.4442C>T, within the acidic domain of HCFC1 gene identified by whole exon sequencing (WES) and validated by Sanger sequencing.
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Prevalence and Genetic Profile of β-Thalassemia Associated Mutations in a Mauritanian Population

Although common in the Mediterranean populations, β-thalassemia are present in various other parts of the world including south Asia and Africa. This study was aimed to re-evaluate the prevalence of β thalassemia, the specific underlying β globin gene mutations and their associated haplotypes in the Mauritanian population.
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Canavan Disease (Aspartoacylase Deficiency): Report of the First Case in Basque Country and a Novel Mutation in Europe

Canavan disease, a genetic and metabolic neurodegenerative disorder, occurs at early ages, causing visual, neurological alterations, and fatal consequences. There is no curative treatment, although lithium citrate is being investigated. This is the first case reported in the Basque region of Spain and it introduces a novel mutation to Europe.
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Case Report of Novel LAMB2 Gene Mutation in Palestinian Infant with Pierson (Microcoria-Congenital Nephrosis) Syndrome

Laminin β2 (LAMB2) gene mutation typically causes a rare autosomal recessive inherited disorder called Pierson syndrome (PS) that present in the neonatal period and progressively affecting renal and ocular functions in the form of congenital nephrotic syndrome (CNS) combined with bilateral microcoria.
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An Insight into the Role of Spliceosomal Mutations in Myelodysplastic Syndromes

The identification of altered splicing signatures in Myelodysplastic Syndromes (MDS) could likely provide key markers for diagnosis, prognostication and development of novel therapeutics. This review presents an insight into role of spliceosomal gene mutations in the pathogenesis of MDS, emphasizing on their clinical and prognostic significance. We also discuss emerging studies delineating the functional consequences of these mutations and pointing towards the emergence of a new leukemogenic pathway involving spliceosomal dysfunction.
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Inherited Thrombophilia Could be a Possible Rare Etiology to Result in Cirrhosis: A Case Report and Literature Review

We reported on a cirrhosis patient who was demonstrated on gene sequencing to have inherited thrombophilia. A 33-year-old male patient with 8-year recurrent abdominal distention, symptom aggravated with 4-month pitting edema of lower extremities bilaterally, was identified decompensated cirrhosis in local hospital.
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Mechanisms of Resistance to Kinase Inhibitors and Strategies to Prevent the Development of Drug Resistance

Targeting mutant proteins and associated signaling pathways of driver oncogenes by small molecule kinase inhibitors (KIs) are a promising strategy of cancer therapy. However, despite the initial success of treatment, KIs often become ineffective as intrinsic and acquired resistance. This article reviews the English-language literature to explore the underlying mechanisms of drug resistance and to present a challenge for developing drugs to overcome resistance. Mechanisms of acquired resistance include 1) the selection of pre-existing subclones with other mutations, 2) the emergence of secondary mutations in the target kinase domain, 3) upregulation of kinases both within the same kinase family and their related kinase families, as well as activation of alternative bypass pathways, 4) epithelial-mesenchymal transition, 5) overexpression of pro-survival Bcl-2 family proteins and 6) drug efflux mechanisms. Currently available methods are to obtain tumor biopsy samples at recurrence or progression if the tumor lesion is accessible to a biopsy and to use the second- and third-generation KIs based on the individual need of each patient. Furthermore, recent computational challenges provide design principles to prevent the development of drug resistance. In conclusion, we provide an overview of the postulated resistance mechanisms and highlight the future direction of computational structure-based design of new potent KIs.
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HIV-1 Molecular Characterization and Transmitted Drug Resistance Prevalence among Treatment-Naïve Individuals

The distribution of different human immunodeficiency virus type 1 (HIV-1) genotypes and the prevalence of transmitted drug resistance (TDR) mutations vary greatly across different Brazilian regions. This study aimed to describe the HIV-1 molecular diversity and TDR prevalence among treatment-naïve HIV-1 infected individuals in an urban area of Northeastern Brazil. DNA samples from 97 infected individuals were obtained and pol sequences were generated by Polimerase Chain Reaction (PCR) and direct sequencing. Bioinformatics tools were used to identify the presence of associated mutations with drug resistance, to reconstruct the phylogeny and to detect recombination.
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Pulmonary Adenocarcinoma Transforming into Small Cell Carcinoma: An Extreme Rarity

Primary small cell lung cancer (SCLC) showing epidermal growth factor receptor (EGFR) mutation is extremely rare. Transformation into SCLC has been reported as an evolution of lung adenocarcinoma acquiring resistance to EGFR tyrosine kinase inhibitors (TKI) and is considered to be a rare resistance mechanism of EGFR-TKI therapy.
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Responses and Survival under Pegylated Interferon α2a Treatment for Patients with Post-MPN Acute Myeloid Leukemia and Acute Panmyelosis with Myelofibrosis

We report here for the first time the efficacy of pegylated interferon α2a (Peg-Ifn) as a therapy for patients with myelofibrosis and high blast counts. We treated four patients who were in an accelerated phase of myeloproliferative neoplasms or acute panmyelosis with myelofibrosis using only this drug.
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Editorial Board Members Related to Mutation

Nejat Dalay

Professor
Istanbul University Oncology Institute
Turkey

Mohamed A Sabry

Associate Professor
Biochemistry Department
Arabian Gulf University
Bahrain

PATRICIA A. KRUK

Professor
Department of Obstetrics and Gynecology
USF Morsani College of Medicine
University of South Florida
United States

Aladin M Boriek

Professor
Department of Medicine
Baylor College of Medicine
United States

Bidyut Roy

Professor
Human Genetics Unit
Indian Statistical Institute
India

SONAL GUPTA

Assistant Professor
Department of Pathology
University of Texas MD Anderson Cancer Center
United States

Yan Guo

Assistant Professor
Center for Quantitative Sciences
Vanderbilt University
United States

Guey-Jen Lee-Chen

Professor
Department of Life Science
National Taiwan Normal University
Taiwan

Boris A. Reva

Associate Professor
Department of Genetics and Genomics Sciences
Icahn School of Medicine at Mount Sinai
United States

Subash Sad

Professor
Department of Biochemistry, Microbiology and Immunology
University of Ottawa
Canada
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