A nonsynonymous LNK polymorphism associated with idiopathic erythrocytosis.
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ABSTRACT:
SUBMITTER: McMullin MF
PROVIDER: S-EPMC3674579 | biostudies-literature | 2011 Nov
REPOSITORIES: biostudies-literature
Publications
A nonsynonymous LNK polymorphism associated with idiopathic erythrocytosis.
McMullin Mary Frances MF Wu Chao C Percy Melanie J MJ Tong Wei W
American journal of hematology 20110822 11
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Project description: Not available
| S-EPMC3762108 | biostudies-literature
Project description:BackgroundErythrocytosis is a condition with an excessive number of erythrocytes, accompanied by an elevated haemoglobin and/or haematocrit value. Congenital erythrocytosis has a diverse genetic background with several genes involved in erythropoiesis. In clinical practice, nine genes are usually examined, but in approximately 70% of patients, no causative mutation can be identified. In this study, we screened 39 genes, aiming to identify potential disease-driving variants in the family with erythrocytosis of unknown cause.Patients and methodsTwo affected family members with elevated haemoglobin and/or haematocrit and negative for acquired causes and one healthy relative from the same family were selected for molecular-genetic analysis of 24 erythrocytosis and 15 hereditary haemochromatosis-associated genes with targeted NGS. The identified variants were further analysed for pathogenicity using various bioinformatic tools and review of the literature.ResultsOf the 12 identified variants, two heterozygous variants, the missense variant c.471G>C (NM_022051.2) (p.(Gln157His)) in the EGLN1 gene and the intron variant c.2572-13A>G (NM_004972.3) in the JAK2 gene, were classified as low-frequency variants in European population. None of the two variants were present in a healthy family member. Variant c.2572-13A>G has potential impact on splicing by one prediction tool.ConclusionFor the first time, we included 39 genes in the erythrocytosis clinical panel and identified two potential disease-driving variants in the Slovene family studied. Based on the reported functional in vitro studies combined with our bioinformatics analysis, we suggest further functional analysis of variant in the JAK2 gene and evaluation of a cumulative effect of both variants.
| S-EPMC8059723 | biostudies-literature
Project description:Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, < 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.
| S-EPMC10799805 | biostudies-literature
Project description: Not available
| S-EPMC5210256 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. Hyaluronidase 1 (HYAL1) was found to be upregulated in fibroblasts from IPF patients, and overexpression of HYAL1 could prevent human fetal lung fibroblast proliferation. However, the genetic correlation between the HYAL1 and IPF or connective tissue diseases related interstitial lung disease (CTD-ILD) has not been determined.MethodsA two-stage study was conducted in Southern Han Chinese population. We sequenced the coding regions and flanking regulatory regions of HYAL1 in stage one (253 IPF cases and 125 controls). A statistically significant variant was further genotyped in stage two (162 IPF cases, 182 CTD-ILD cases, and 225 controls).ResultsWe identified a nonsynonymous polymorphism (rs117179004, T392M) significantly associated with increased IPF risk (dominant model: OR = 2.239, 95% CI = 1.212-4.137, p = 0.010 in stage one; OR = 2.383, 95% CI = 1.376-4.128, p = 0.002 in stage two). However, we did not observe this association in CTD-ILD (OR = 1.401, 95% CI = 0.790-2.485, p = 0.248).ConclusionOur findings suggest that the nonsynonymous polymorphism (rs117179004, T392M) may confer susceptibility to IPF in Southern Han Chinese, but is not associated with susceptibility to CTD-ILD.
| S-EPMC8183947 | biostudies-literature
Project description:The term "idiopathic erythrocytosis (IE)" is applied to those cases where a causal clinical or pathological event cannot be elucidated and likely reflects a spectrum of underlying medical and molecular abnormalities. The clinical course of a patient with IE is described manifesting as a persistent erythrocytosis with a low serum erythropoietin level, mild eosinophilia, and with evidence of a thrombotic event. The patient subsequently developed a myelodysplasic syndrome (MDS) and acute myeloid leukemia (AML), an event not observed in erythrocytosis patients other than those with polycythemia vera (PV). Application of a next-generation sequencing (NGS) approach targeted for myeloid malignancies confirmed wild-type JAK2 exons 12-15 and identified a common SH2B3 W262R single-nucleotide polymorphism associated with the development of hematological features of myeloproliferative neoplasms (MPNs). Further NGS analysis detected a CBL L380P mutated clone expanding in parallel with the development of MDS and subsequent AML. Despite the absence of JAK2, MPL exon 10, or CALR exon 9 mutations, a similarity with the disease course of PV/MPN was evident. A clonal link between the erythrocytosis and AML could be neither confirmed nor excluded. Future molecular identification of the mechanisms underlying IE is likely to provide a more refined therapeutic approach.
| S-EPMC5842720 | biostudies-literature
Project description:BackgroundErythrocytosis is a hematological disorder usually related to hematopoietic stem cell somatic mutations. However, unexplained erythrocytosis remains frequent. In this study, we evaluated the involvement of IgA1, a regulator of erythropoiesis also implicated in IgA nephropathy (IgAN) pathophysiology, in unexplained polycythemia/erythrocytosis (PE) of IgAN patients.MethodsIgAN-PE patients' serum was collected, analyzed and used to study IgA1 effect on proliferation and differentiation of erythroid progenitors. Hematological parameters of transgenic mice for human alpha1 heavy chain were studied. Multicentric observational cohorts of chronic kidney disease (CKD) patients, including both native kidney diseases and renal transplants, were studied to analyze patient hemoglobin levels.FindingsWe retrospectively identified 6 patients with IgAN and unexplained PE. In large CKD cohorts, IgAN was associated with PE in 3.5% of patients (p<0.001 compared to other nephropathies). IgAN was an independent factor associated with higher hemoglobin levels (13.1g/dL vs 12.2 g/dL, p=0.01). During post-transplant anemia, anemia recovery was faster in IgAN patients. Elevated polymeric/monomeric IgA1 ratio as well as high Gd-IgA1 rate were observed in circulating IgA1 of the 6 IgAN-PE patients as compared with control or IgAN patients without PE. IgA1 from these patients increased the sensitivity of erythroid progenitors to Epo. In mice, we also observed an elevation of hematocrit in alpha1 knock-in mice compared to wild type controls.InterpretationThese data identify a new etiology of erythrocytosis and demonstrate the role of pIgA1 in human erythropoiesis. This syndrome of IgA-related erythrocytosis should be investigated in case of unexplained erythrocytosis and renal disease.FundingThis work was supported by INSERM (French national institute for health and medical research), Labex GRex and Imagine Institute (Paris, France).
| S-EPMC8718985 | biostudies-literature
Project description: Not available
| S-EPMC11462191 | biostudies-literature
Project description:Erythrocytosis or polycythemia refers to a true or apparent increase in hemoglobin or hematocrit. When no etiology of erythrocytosis is identified, people are diagnosed with "idiopathic erythrocytosis" (IE). The identification of new contributing genes has recently improved the diagnostic workup of IE. As such mutations within the SH2B3 gene, which codes for the LNK protein and negatively regulates the JAK-STAT pathway, have been identified in cases diagnosed as IE. This reports describes the presence of a previously undescribed germline SH2B3 variant p.(Thr335ArgfsTer4) within IE and emphasizes the advantages of gene panel sequencing as second step in the diagnostic work-up.
| S-EPMC10660405 | biostudies-literature
Project description:Genomic data reveal single-nucleotide polymorphisms (SNPs) that may carry information about the evolutionary history of bacteria. However, it remains unclear what inferences about selection can be made from genomic SNP data. Bacterial species are often sampled during epidemic outbreaks or within hosts during the course of chronic infections. SNPs obtained from genomic analysis of these data are not necessarily fixed. Treating them as fixed during analysis by using measures such as the ratio of nonsynonymous to synonymous evolutionary changes (dN/dS) may lead to incorrect inferences about the strength and direction of selection. In this study, we consider data from a range of whole-genome sequencing studies of bacterial pathogens and explore patterns of nonsynonymous variation to assess whether evidence of selection can be identified by investigating SNP counts alone across multiple WGS studies. We visualize these SNP data in ways that highlight their relationship to neutral baseline expectations. These neutral expectations are based on a simple model of mutation, from which we simulate SNP accumulation to investigate how SNP counts are distributed under alternative assumptions about positive and negative selection. We compare these patterns with empirical SNP data and illustrate the general difficulty of detecting positive selection from SNP data. Finally, we consider whether SNP counts observed at the between-host population level differ from those observed at the within-host level and find some evidence that suggests that dynamics across these two scales are driven by different underlying processes.IMPORTANCE Identifying selection from SNP data obtained from whole-genome sequencing studies is challenging. Some current measures used to identify and quantify selection acting on genomes rely on fixed differences; thus, these are inappropriate for SNP data where variants are not fixed. With the increase in whole-genome sequencing studies, it is important to consider SNP data in the context of evolutionary processes. How SNPs are counted and analyzed can help in understanding mutation accumulation and trajectories of strains. We developed a tool for identifying possible evidence of selection and for comparative analysis with other SNP data. We propose a model that provides a rule-of-thumb guideline and two new visualization techniques that can be used to interpret and compare SNP data. We quantify the expected proportion of nonsynonymous SNPs in coding regions under neutrality and demonstrate its use in identifying evidence of positive and negative selection from simulations and empirical data.
| S-EPMC7755258 | biostudies-literature