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HCMV UL97 phosphotransferase gene mutations may be associated with antiviral resistance in immunocompromised patients in Belém, PA, Northern Brazil.
Silva, DFLD, Cardoso, JF, Silva, SPD, Arruda, LMF, Medeiros, RLF, Moraes, MM, Sousa, RCM
Revista da Sociedade Brasileira de Medicina Tropical. 2018;(2):141-145
Abstract
INTRODUCTION Human cytomegalovirus is one of the causes of opportunist infections in immunocompromised patients, and is triggered by factors such as state of viral latency, weakened immune responses, and development of antiviral resistance to ganciclovir, the only drug offered by the public health system in Brazil to treat the infection. The goal of this study was to identify mutations that may be associated with antiviral resistance in immunocompromised patients. METHODS Molecular analysis was performed in 82 blood samples and subjected to genomic DNA extraction by a silica-based method. Three sequences of the HCMV UL97 gene, which encodes a phosphotransferase protein required for activation of ganciclovir, were amplified by polymerase chain reaction. Pyrosequencing methods were applied to one external 2096-bp segment DNA and two internal sequences between nucleotides 1087 to 1828 to detect mutations in this gene. RESULTS Approximately 10% of sequences contained mutations between nucleotides 377 and 594, in conserved regions of the UL97 gene, leading to amino acid changes. Eleven coding mutations were identified, including changes leading to amino acid substitutions, E596K and S604F, which were observed in 100% of samples and are described for the first time in Brazil. In addition, one mutation (A594V) that is associated with ganciclovir resistance was detected in a kidney transplant patient. CONCLUSIONS Further studies to detect mutations associated with HCMV resistance to antiviral drugs are required to demonstrate the need to increase the variety and availability of drugs used to treat viral infections in the public health care system in Brazil.
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Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage.
Xu, H, Schmidt, AG, O'Donnell, T, Therkelsen, MD, Kepler, TB, Moody, MA, Haynes, BF, Liao, HX, Harrison, SC, Shaw, DE
Proteins. 2015;(4):771-80
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Abstract
Affinity maturation, the process in which somatic hypermutation and positive selection generate antibodies with increasing affinity for an antigen, is pivotal in acquired humoral immunity. We have studied the mechanism of affinity gain in a human B-cell lineage in which two main maturation pathways, diverging from a common ancestor, lead to three mature antibodies that neutralize a broad range of H1 influenza viruses. Previous work showed that increased affinity in the mature antibodies derives primarily from stabilization of the CDR H3 loop in the antigen-binding conformation. We have now used molecular dynamics simulations and existing crystal structures to identify potentially key maturation mutations, and we have characterized their effects on the CDR H3 loop and on antigen binding using further simulations and experimental affinity measurements, respectively. In the two maturation pathways, different contacts between light and heavy chains stabilize the CDR H3 loop. As few as two single-site mutations in each pathway can confer substantial loop stability, but none of them confers experimentally detectable stability on its own. Our results support models of the germinal center reaction in which two or more mutations can occur without concomitant selection and show how divergent pathways have yielded functionally equivalent antibodies.
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Common variants of the vitamin D binding protein gene and adverse health outcomes.
Malik, S, Fu, L, Juras, DJ, Karmali, M, Wong, BY, Gozdzik, A, Cole, DE
Critical reviews in clinical laboratory sciences. 2013;(1):1-22
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Abstract
The vitamin D binding protein (DBP) is the major plasma carrier for vitamin D and its metabolites, but it is also an actin scavenger, and is the precursor to the immunomodulatory protein, Gc-MAF. Two missense variants of the DBP gene - rs7041 encoding Asp432Glu and rs4588 encoding Thr436Lys - change the amino acid sequence and alter the protein function. They are common enough to generate population-wide constitutive differences in vitamin D status, based on assay of the serum metabolite, 25-hydroxyvitamin D (25OHD). Whether these variants also influence the role of vitamin D in an immunologic milieu is not known. However, the issue is relevant, given the immunomodulatory effects of DBP and the role of protracted innate immune-related inflammation in response to tissue injury or repeated infection. Indeed, DBP and vitamin D may jointly or independently contribute to a variety of adverse health outcomes unrelated to classical notions of their function in bone and mineral metabolism. This review summarizes the reports to date of associations between DBP variants, and various chronic and infectious diseases. The available information leads us to conclude that DBP variants are a significant and common genetic factor in some common disorders, and therefore, are worthy of closer attention. In view of the heightened interest in vitamin D as a public health target, well-designed studies that look simultaneously at vitamin D and its carrier in relation to genotypes and adverse health outcome should be encouraged.
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Contribution of genetic factors to the pathogenesis of dilated cardiomyopathy: the cause of dilated cardiomyopathy: genetic or acquired? (genetic-side).
Kimura, A
Circulation journal : official journal of the Japanese Circulation Society. 2011;(7):1756-65; discussion 1765
Abstract
Dilated cardiomyopathy (DCM) is characterized by dilated ventricles and systolic dysfunction. Its etiology is not fully unraveled, but both extrinsic and intrinsic factors are considered to be involved. The intrinsic factors include genetic variations in the genes (ie, disease-causing mutations and disease-associated polymorphisms), which play key roles in controlling the susceptibility to the disease by affecting the performance, regulation, and/or maintenance of cardiac function. DCM can be classified into 2 types: hereditary and non-hereditary. The genetic variations, or disease-causing mutations, contributing to the pathogenesis of hereditary DCM can be found in various genes, especially those for sarcolemma elements, contractile elements, Z-disc elements, sarcoplasmic elements, and nuclear lamina elements of cardiomyocytes. On the other hand, disease-associated polymorphisms, which control the susceptibility to non-hereditary DCM, may be found in genes expressing not only in cardiomyocytes but also other non-cardiac cells involved in the immune system. Because functional alterations caused by these genetic variations can be classified into several categories, it is necessary to understand the pathogenesis and hence to develop diagnostic and therapeutic strategies for both hereditary and non-hereditary DCM from the viewpoint of genetic factors.
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PRPS1 mutations: four distinct syndromes and potential treatment.
de Brouwer, AP, van Bokhoven, H, Nabuurs, SB, Arts, WF, Christodoulou, J, Duley, J
American journal of human genetics. 2010;(4):506-18
Abstract
Phosphoribosylpyrophosphate synthetases (PRSs) catalyze the first step of nucleotide synthesis. Nucleotides are central to cell function, being the building blocks of nucleic acids and serving as cofactors in cellular signaling and metabolism. With this in mind, it is remarkable that mutations in phosphoribosylpyrophosphate synthetase 1 (PRPS1), which is the most ubiquitously expressed gene of the three PRS genes, are compatible with life. Mutations described thus far in PRPS1 are all missense mutations that result in PRS-I superactivity or in variable levels of decreased activity, resulting in X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2). Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment. Postlingual progressive hearing loss is found as an isolated feature in DFN2 patients. Patients with CMTX5 and Arts syndrome have peripheral neuropathy, including hearing impairment and optic atrophy. However, patients with Arts syndrome are more severely affected because they also have central neuropathy and an impaired immune system. The neurological phenotype in all four PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in two Arts syndrome patients show improvement of their condition, indicating that SAM supplementation in the diet could alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides (J.C., unpublished data).