Identification of a shared<i>F8</i>mutation in the Korean patients with acquired hemophilia A

Hwang, Sung Ho; Lim, Jeong Ae; Kim, Hugh Chul; Lee, Hyun Woo; Kim, Hye Sun

doi:10.5045/kjh.2011.46.1.49

Cited by 9 publications

(12 citation statements)

References 15 publications

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“…In addition to F8 gene, other molecular mechanisms have, to a limited extent, been explored. In a small cohort study of patients with acquired HA, differentially expressed genes between inhibitor and non-inhibitor patients were identified using gene expression microarray analysis [ 9 ]. Moreover, while very low level of FVIII in plasma is indicative of severe HA, another recent study indicates that platelets in circulation are in a pre-activated state in severe HA patients and these patients were observed to consume lower amounts of FVIII in therapy [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Small ncRNA Expression-Profiling of Blood from Hemophilia A Patients Identifies miR-1246 as a Potential Regulator of Factor 8 Gene

et al. 2015

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Hemophilia A (HA) is a bleeding disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). Genetic mutations in the gene encoding FVIII (F8) have been extensively studied. Over a thousand different mutations have been reported in the F8 gene. These span a diverse range of mutation types, namely, missense, splice-site, deletions of single and multiple exons, inversions, etc. There is nonetheless evidence that other molecular mechanisms, in addition to mutations in the gene encoding the FVIII protein, may be involved in the pathobiology of HA. In this study, global small ncRNA expression profiling analysis of whole blood from HA patients, and controls, was performed using high-throughput ncRNA microarrays. Patients were further sub-divided into those that developed neutralizing-anti-FVIII antibodies (inhibitors) and those that did not. Selected differentially expressed ncRNAs were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. We identified several ncRNAs, and among them hsa-miR-1246 was significantly up-regulated in HA patients. In addition, miR-1246 showed a six-fold higher expression in HA patients without inhibitors. We have identified an miR-1246 target site in the noncoding region of F8 mRNA and were able to confirm the suppressory role of hsa-miR-1246 on F8 expression in a stable lymphoblastoid cell line expressing FVIII. These findings suggest several testable hypotheses vis-à-vis the role of nc-RNAs in the regulation of F8 expression. These hypotheses have not been exhaustively tested in this study as they require carefully curated clinical samples.

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Section: Introductionmentioning

confidence: 99%

Small ncRNA Expression-Profiling of Blood from Hemophilia A Patients Identifies miR-1246 as a Potential Regulator of Factor 8 Gene

et al. 2015

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“…The paradigm of acquired hemophilia has also shifted over the last few years. It was shown that in two acquired hemophilia patients a point mutation was found (c.8899G>A) in the F8 gene (42). As follows, more evidence may come if acquired HA patients will also go through an analysis of the ncRNA or epigenetic mark-up.…”

Section: Aha-a Recently Described Ha With a Non-mutational Backgroundmentioning

confidence: 95%

The Possible Non-Mutational Causes of FVIII Deficiency: Non-Coding RNAs and Acquired Hemophilia A

et al. 2021

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Hemophilia type A (HA) is the most common type of blood coagulation disorder. While the vast majority of cases are inherited and caused by mutations in the F8 gene, recent data raises new questions regarding the non-heritability of this disease, as well as how other molecular mechanisms might lead to the development of HA or increase the severity of the disease. Some data suggest that miRNAs may affect the severity of HA, but for some patients, miRNA-based interference might cause HA, in the absence of an F8 mutation. A mechanism in HA installation that is also worth investigating and which could be identified in the future is the epigenetic silencing of the F8 gene that might be only temporarily. Acquired HA is increasingly reported and as more cases are identified, the description of the disease might become challenging, as cases without FVIII autoantibodies might be identified.

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“…Exon variants in F13A1, F13B, CTLA4, HLA-DRB1, and HLA-DQB1 genes (Selection of Candidate 1). We hypothesized that F13A1 and F13B variants might also be associated with the development of autoantibodies in patients with autoimmune FXIII deficiency as F8 is known to be associated with the development of autoantibodies in patients with AHA [13]. We identified four F13A1 variants and three F13B variants.…”

Section: Selection Of Candidate Alleles Associated With the Development Of Anti-fxiii Autoantibodies In Autoimmune Fxiii Deficiencymentioning

confidence: 98%

“…Approximately 50% of the total cases of acquired hemophilia A (AHA), are considered to be idiopathic [9]. AHA is associated with high frequencies of the human leukocyte antigen (HLA) class II alleles and single nucleotide polymorphisms (SNPs) of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene [9][10][11][12][13]. These genetic factors are also associated with the development of factor VIII inhibitors in patients with severe hemophilia A [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Important roles of the human leukocyte antigen class I and II molecules and their associated genes in the autoimmune coagulation factor XIII deficiency via whole-exome sequencing analysis

2021

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Autoimmune coagulation factor XIII deficiency is a bleeding disorder caused by the formation of autoantibodies against the coagulation factor XIII (FXIII); however, the molecular mechanism underlying this process is unknown. Therefore, in the present study, we aimed to elucidate this mechanism by performing whole-exome sequencing analysis of 20 cases of autoimmune FXIII deficiency. We identified approximately 21,788–23,916 variants in each case. In addition to their ability to activate T cells, present antigens, and immune tolerance, the candidate alleles were further narrowed down according to their allelic frequencies and the magnitude of damage caused by the substitution of amino acids. After selecting 44 candidate alleles, we investigated whether they were associated with the FXIII inhibitory titers and/or the anti-FXIII autoantibodies. We found that two polymorphisms whose variant allele frequencies were significantly lower in the patients tended to decrease FXIII inhibitory titers as the number of variant alleles increased. We also found that five polymorphisms whose variant allele frequencies were significantly higher in the patients tended to increase the levels of the anti-FXIII autoantibodies as the number of variant alleles increased. All of these polymorphisms were found in the human leukocyte antigen (HLA) class I and II molecules and their associated genes. In particular, the HLA class II molecule and its associated genes were found to be involved in the presentation of foreign antigens as well as the negative regulation of the proliferation of T-cells and the release of cytokines. Polymorphisms in the HLA class II molecules and the cytotoxic T lymphocyte antigen 4 have been reported to be associated with the development of autoantibodies in acquired hemophilia A. Therefore, we hypothesized that these polymorphisms may be associated with the development of autoantibodies in autoimmune FXIII deficiency.

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Identification of a sharedF8mutation in the Korean patients with acquired hemophilia A

Cited by 9 publications

References 15 publications

Small ncRNA Expression-Profiling of Blood from Hemophilia A Patients Identifies miR-1246 as a Potential Regulator of Factor 8 Gene

Small ncRNA Expression-Profiling of Blood from Hemophilia A Patients Identifies miR-1246 as a Potential Regulator of Factor 8 Gene

The Possible Non-Mutational Causes of FVIII Deficiency: Non-Coding RNAs and Acquired Hemophilia A

Important roles of the human leukocyte antigen class I and II molecules and their associated genes in the autoimmune coagulation factor XIII deficiency via whole-exome sequencing analysis

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