scholarly journals Recent Advances in the Molecular Biology of Systemic Mastocytosis: Implications for Diagnosis, Prognosis, and Therapy

2020 ◽  
Vol 21 (11) ◽  
pp. 3987 ◽  
Author(s):  
Margherita Martelli ◽  
Cecilia Monaldi ◽  
Sara De Santis ◽  
Samantha Bruno ◽  
Manuela Mancini ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Systemic Mastocytosis ◽  
Gene Mutations ◽  
Scoring Systems ◽  
Molecular Data ◽  
Loss Of Function ◽  
Prognostic Information ◽  
Genetic Profiling ◽  
Kit D816v

In recent years, molecular characterization and management of patients with systemic mastocytosis (SM) have greatly benefited from the application of advanced technologies. Highly sensitive and accurate assays for KIT D816V mutation detection and quantification have allowed the switch to non-invasive peripheral blood testing for patient screening; allele burden has prognostic implications and may be used to monitor therapeutic efficacy. Progress in genetic profiling of KIT, together with the use of next-generation sequencing panels for the characterization of associated gene mutations, have allowed the stratification of patients into three subgroups differing in terms of pathogenesis and prognosis: (i) patients with mast cell-restricted KIT D816V; (ii) patients with multilineage KIT D816V-involvement; (iii) patients with “multi-mutated disease”. Thanks to these findings, new prognostic scoring systems combining clinical and molecular data have been developed. Finally, non-genetic SETD2 histone methyltransferase loss of function has recently been identified in advanced SM. Assessment of SETD2 protein levels and activity might provide prognostic information and has opened new research avenues exploring alternative targeted therapeutic strategies. This review discusses how progress in recent years has rapidly complemented previous knowledge improving the molecular characterization of SM, and how this has the potential to impact on patient diagnosis and management.

scholarly journals New developments in diagnosis, prognostication, and treatment of advanced systemic mastocytosis

Blood ◽  
2020 ◽  
Vol 135 (16) ◽  
pp. 1365-1376 ◽  
Author(s):  
Andreas Reiter ◽  
Tracy I. George ◽  
Jason Gotlib
Keyword(s):  
Mast Cell ◽  
Systemic Mastocytosis ◽  
Scoring Systems ◽  
Molecular Data ◽  
Genetic Profiling ◽  
Switch Control ◽  
Genetic Landscape ◽  
Mast Cell Disease ◽  
Next Generation Sequencing Ngs ◽  
Kit D816v

Abstract Systemic mastocytosis (SM) has greatly benefited from the broad application of precision medicine techniques to hematolymphoid neoplasms. Sensitive detection of the recurrent KIT D816V mutation and use of next-generation sequencing (NGS) panels to profile the genetic landscape of SM variants have been critical adjuncts to the diagnosis and subclassification of SM, and development of clinical-molecular prognostic scoring systems. Multilineage KIT involvement and multimutated clones are characteristic of advanced SM (advSM), especially SM with an associated hematologic neoplasm (AHN). A major challenge is how to integrate conventional markers of mast cell disease burden (percentage of bone marrow mast cell infiltration and serum tryptase levels) with molecular data (serial monitoring of both KIT D816V variant allele frequency and NGS panels) to lend more diagnostic and prognostic clarity to the heterogeneous clinical presentations and natural histories of advSM. The approval of the multikinase/KIT inhibitor midostaurin has validated the paradigm of KIT inhibition in advSM, and the efficacy and safety of second-generation agents, such as the switch-control inhibitor ripretinib (DCC-2618) and the D816V-selective inhibitor avapritinib (BLU-285) are being further defined in ongoing clinical trials. Looking forward, perhaps the most fruitful marriage of the advances in molecular genetics and treatment will be the design of adaptive basket trials that combine histopathology and genetic profiling to individualize treatment approaches for patients with diverse AHNs and relapsed/refractory SM.

Clinical and molecular characterization of de novo loss of function variants inHNRNPU

2017 ◽  
Vol 173 (10) ◽  
pp. 2680-2689 ◽  
Author(s):  
Magalie S. Leduc ◽  
Hsiao-Tuan Chao ◽  
Chunjing Qu ◽  
Magdalena Walkiewicz ◽  
Rui Xiao ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
De Novo ◽  
Loss Of Function

scholarly journals Molecular characterization and distribution of Plasmodium matutinum, a common avian malaria parasite

Parasitology ◽  
2017 ◽  
Vol 144 (13) ◽  
pp. 1726-1735 ◽  
Author(s):  
GEDIMINAS VALKIŪNAS ◽  
MIKAS ILGŪNAS ◽  
DOVILĖ BUKAUSKAITĖ ◽  
VAIDAS PALINAUSKAS ◽  
RASA BERNOTIENĖ ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Molecular Characterization ◽  
Malaria Parasite ◽  
Avian Malaria ◽  
Clinical Signs ◽  
Molecular Data ◽  
Infected Blood ◽  
Avian Malaria Parasite ◽  
Thrush Nightingale

SUMMARYSpecies of Plasmodium (Plasmodiidae, Haemosporida) are widespread and cause malaria, which can be severe in avian hosts. Molecular markers are essential to detect and identify parasites, but still absent for many avian malaria and related haemosporidian species. Here, we provide first molecular characterization of Plasmodium matutinum, a common agent of avian malaria. This parasite was isolated from a naturally infected thrush nightingale Luscinia luscinia (Muscicapidae). Fragments of mitochondrial, apicoplast and nuclear genomes were obtained. Domestic canaries Serinus canaria were susceptible after inoculation of infected blood, and the long-lasting light parasitemia developed in two exposed birds. Clinical signs of illness were not reported. Illustrations of blood stages of P. matutinum (pLINN1) are given, and phylogenetic analysis identified the closely related avian Plasmodium species. The phylogeny based on partial cytochrome b (cyt b) sequences suggests that this parasite is most closely related to Plasmodium tejerai (cyt b lineage pSPMAG01), a common malaria parasite of American birds. Both these parasites belong to subgenus Haemamoeba, and their blood stages are similar morphologically, particularly due to marked vacuolization of the cytoplasm in growing erythrocytic meronts. Molecular data show that transmission of P. matutinum (pLINN1) occurs broadly in the Holarctic, and the parasite likely is of cosmopolitan distribution. Passeriform birds and Culex mosquitoes are common hosts. This study provides first molecular markers for detection of P. matutinum.

Molecular Characterization of β- and α-Globin Gene Mutations in Individuals with Borderline Hb A2 Levels

Hemoglobin ◽  
2020 ◽  
Vol 44 (5) ◽  
pp. 349-353
Author(s):  
Surada Satthakarn ◽  
Sitthichai Panyasai ◽  
Sakorn Pornprasert
Keyword(s):  
Molecular Characterization ◽  
Globin Gene ◽  
Gene Mutations

scholarly journals Molecular Characterization of eutF Mutants ofSalmonella typhimurium LT2 Identifies eutFLesions as Partial-Loss-of-Function tonB Alleles

1999 ◽  
Vol 181 (2) ◽  
pp. 368-374 ◽  
Author(s):  
Michael G. Thomas ◽  
George A. O’Toole ◽  
Jorge C. Escalante-Semerena
Keyword(s):  
Amino Acid ◽  
Molecular Characterization ◽  
Immunoblot Analysis ◽  
Phenotypic Characterization ◽  
Loss Of Function ◽  
Wild Type ◽  
Partial Loss ◽  
Acid Addition ◽  
Fusion Site

ABSTRACT The eutF locus of Salmonella typhimuriumLT2 was identified as a locus necessary for the utilization of ethanolamine as a sole carbon source. Initial models suggested that EutF was involved in either ethanolamine transport or was a transcriptional regulator of an ethanolamine transporter. Phenotypic characterization of eutF mutants suggested EutF was somehow involved in 1,2-propanediol, propionate, and succinate utilization. Here we provide evidence that two alleles defining the eutFlocus, Δ903 and eutF1115, are partial-loss-of-function tonB alleles. Both mutations were complemented by plasmids containing a wild-type allele of theEscherichia coli tonB gene. Immunoblot analysis using TonB monoclonal antibodies detected a TonB fusion protein in strains carrying eutF alleles. Molecular analysis of the Δ903 allele identified a deletion that resulted in the fusion of the 3′ end of tonB with the 3′ end oftrpA. In-frame translation of the tonB-trpAfusion resulted in the final 9 amino acids of TonB being replaced by a 45-amino-acid addition. We isolated a derivative of a strain carrying allele Δ903 that regained the ability to grow on ethanolamine as a carbon and energy source. The molecular characterization of the mutation that corrected the Eut−phenotype caused by allele Δ903 showed that the new mutation was a deletion of two nucleotides at the tonB-trpAfusion site. This deletion resulted in a frameshift that replaced the 45-amino-acid addition with a 5-amino-acid addition. This change resulted in a TonB protein with sufficient activity to restore growth on ethanolamine and eut operon expression to nearly wild-type levels. It was concluded that the observed EutF phenotypes were due to the partial loss of TonB function, which is proposed to result in reduced cobalamin and ferric siderophore transport in an aerobic environment; thus, the eutF locus does not exist.

scholarly journals Molecular characterization of G6PD mutations reveals the high frequency of G6PD Aures in the Lao Theung population 

2020 ◽  
Author(s):  
Amkha Sanephonasa ◽  
Chalisa Louicharoen Cheepsunthorn ◽  
Naly Khaminsou ◽  
Onekham Savongsy ◽  
Issarang Nuchprayoon ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Ethnic Group ◽  
Molecular Characterization ◽  
G6pd Deficiency ◽  
Gene Mutations ◽  
Final Diagnosis ◽  
Amplification Refractory Mutation System ◽  
Common Mutation ◽  
Arms Pcr

Abstract Background: The prevalence and genotypes of G6PD deficiency vary worldwide, with higher prevalence in malaria endemic areas. The first time assessment of G6PD deficiency prevalence and molecular characterization of G6PD mutations in the Lao Theung population were performed in this study. Methods: A total of 252 unrelated Lao Theung participants residing in the Lao People's Democratic Republic (PDR) were recruited. All participant samples were tested for G6PD enzyme activity and G6PD gene mutations. The amplification refractory mutation system (ARMS)-PCR for detecting G6PD Aures was developed.Results: The G6PD mutations were detected in 11.51% (29/252) of the participants. Eight G6PD mutations were detected. The G6PD Aures was the most common mutation identified in this cohort, which represented 58.62 % (17/29) of all mutation. The mutation pattern was homogenous, predominantly involving the G6PD Aures mutation (6.75%), followed by 1.19% G6PD Union and 0.79% each G6PD Jammu, G6PD Mahidol and G6PD Kaiping. One subject (0.4%) each carried G6PD Viangchan and G6PD Canton. Interestingly, one case of coinheritance of G6PD Aures and Quing Yan was detected in this cohort. Based on levels of G6PD enzyme activity, the prevalence of G6PD deficiency in the Lao Theung population was 9.13 % (23/252). The prevalence of G6PD deficient males and females (activity < 30 %) in the Lao Theung population was 6.41 % (5/78) and 1.72 % (3/174), respectively, and the prevalence of G6PD intermediate (activity 30-70 %) was 5.95 % (15/252).Conclusion: The G6PD Aures mutation is highly prevalent in the Lao Theung ethnic group. The common G6PD variants in continental Southeast Asian populations, G6PD Viangchan, Canton, Kaiping, Union and Mahidol, were not prevalent in this ethnic group. The technical simplicity of the developed ARMS-PCR will facilitate the final diagnosis of the G6PD Aures.

scholarly journals Molecular characterization of G6PD mutations reveals the high frequency of G6PD Aures in the Lao Theung population

2021 ◽  
Author(s):  
Amkha Sanephonasa ◽  
Chalisa Louicharoen Cheepsunthorn ◽  
Naly Khaminsou ◽  
Onekham Savongsy ◽  
Issarang Nuchprayoon ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Ethnic Group ◽  
Molecular Characterization ◽  
G6pd Deficiency ◽  
Gene Mutations ◽  
Final Diagnosis ◽  
Amplification Refractory Mutation System ◽  
Common Mutation ◽  
Arms Pcr

Abstract Background The prevalence and genotypes of G6PD deficiency vary worldwide, with higher prevalence in malaria endemic areas. The first-time assessment of G6PD deficiency prevalence and molecular characterization of G6PD mutations in the Lao Theung population were performed in this study. Methods A total of 252 unrelated Lao Theung participants residing in the Lao People's Democratic Republic (PDR) were recruited. All participant samples were tested for G6PD enzyme activity and G6PD gene mutations. The amplification refractory mutation system (ARMS)-PCR for detecting G6PD Aures was developed.Results The G6PD mutations were detected in 11.51% (29/252) of the participants. Eight G6PD mutations were detected. The G6PD Aures was the most common mutation identified in this cohort, which represented 58.62 % (17/29) of all mutation. The mutation pattern was homogenous, predominantly involving the G6PD Aures mutation (6.75%), followed by 1.19% G6PD Union and 0.79% each G6PD Jammu, G6PD Mahidol and G6PD Kaiping. One subject (0.4%) each carried G6PD Viangchan and G6PD Canton. Interestingly, one case of coinheritance of G6PD Aures and Quing Yan was detected in this cohort. Based on levels of G6PD enzyme activity, the prevalence of G6PD deficiency in the Lao Theung population was 9.13 % (23/252). The prevalence of G6PD deficient males and females (activity < 30 %) in the Lao Theung population was 6.41 % (5/78) and 1.72 % (3/174), respectively, and the prevalence of G6PD intermediate (activity 30-70 %) was 5.95 % (15/252).Conclusion The G6PD Aures mutation is highly prevalent in the Lao Theung ethnic group. The common G6PD variants in continental Southeast Asian populations, G6PD Viangchan, Canton, Kaiping, Union and Mahidol, were not prevalent in this ethnic group. The technical simplicity of the developed ARMS-PCR will facilitate the final diagnosis of the G6PD Aures.

scholarly journals Morphology and molecular characterization of Demidospermus spirophallus n. sp., D. prolixus n. sp. (Monogenea: Dactylogyridae) and a redescription of D. anus in siluriform catfish from Brazil

2017 ◽  
Vol 92 (2) ◽  
pp. 228-243 ◽  
Author(s):  
L. Franceschini ◽  
A.C. Zago ◽  
M.I. Müller ◽  
C.J. Francisco ◽  
R.M. Takemoto ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Accessory Piece ◽  
Copulatory Organ ◽  
Molecular Data ◽  
Neotropical Region ◽  
Morphological Characterization ◽  
Ribosomal Gene ◽  
Upper Paraná River Floodplain ◽  
Morphological And Molecular Data

AbstractThe present study describes Demidospermus spirophallus n. sp. and Demidospermus prolixus n. sp. (Monogenea, Dactylogyridae) from the siluriform catfish Loricaria prolixa Isbrücker & Nijssen, 1978 (Siluriformes, Loricariidae) from the state of São Paulo, Brazil, supported by morphological and molecular data. In addition, notes on the circumscription of the genus with a redescription of Demisdospermus anus are presented. Demidospermus spirophallus n. sp. differed from other congeners mainly because of the morphology of the male copulatory organ (MCO), which exhibited 2½ counterclockwise rings, a tubular accessory piece with one bifurcated end and a weakly sclerotized vagina with sinistral opening. Demidospermus prolixus n. sp. presents a counterclockwise-coiled MCO with 1½ rings, an ovate base, a non-articulated groove-like accessory piece serving as an MCO guide, two different hook shapes, inconspicuous tegumental annulations, a non-sclerotized vagina with sinistral opening and the absence of eyes or accessory eyespots. The present study provides, for the first time, molecular characterization data using the partial ribosomal gene (28S) of two new species of Demidospermus from Brazil (D. spirophallus n. sp. and D. prolixus n. sp.), and Demidospermus anus from Loricariichthys platymetopon Isbrücker & Nijssen, 1979 collected in the Upper Paraná River floodplain, Brazil. Additionally, a revision of the species composition of this genus and others that occur in catfish is proposed to elucidate problems with their circumscription. The Brazilian species of Demidospermus clustered together as sister taxa among Neotropical dactylogyrids from siluriforms. The morphological characterization of D. spirophallus n. sp. and D. prolixus n. sp., and the molecular data of the three species in the present study will extend knowledge about this monogenean genus from the Neotropical region, and provide new information for future phylogeny studies.

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