Analysis of F9 point mutations and their correlation to severity of haemophilia B disease

Hamasaki-Katagiri, Nobuko; Salari, Raheleh; Simhadri, Vijaya L.; Tseng, Shi‐Chang; Needlman, E.; Edwards, Nathan C.; Sauna, Zuben E.; Grigoryan, Vahan; Komar, Anton A.; Przytycka, Teresa M.; Kimchi-Sarfaty, Chava

doi:10.1111/j.1365-2516.2012.02848.x

Cited by 12 publications

(17 citation statements)

References 19 publications

(20 reference statements)

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“…On the nucleotide level, the mutation position in the codon, type of nucleotide change (transition/transversion), codon usage (RSCU), and Gibbs free energy of mRNA fragments are clearly shown to have highly positive associations. Several of these measurements were also previously indicated to have functional impacts on other proteins [22,15] and have been emphasized further in this study. The significance of codon usage, represented by RSCU, suggests that the balance of supply and demand of specific aminoacyl-tRNA might affect the local translation rate/rhythm.…”

Section: Discussionmentioning

confidence: 56%

“…The remaining mutations are all used to test the classifier. To further evaluate our model, we applied it to the set of HB-causing f9 mutations previously collected, in addition to all neutral f9 variants chosen from the dbSNP database [15]. Composition details of this dataset, which contains both non-synonymous and synonymous point mutations, are also reported in Table 4.…”

Section: Methodsmentioning

confidence: 99%

“…We used the largest possible collection of point mutations found in HB patients [15]. Despite the modest size of the analyzed cohort (131 unique mutations), this study demonstrated positive correlations between the disease severity and certain parameters at the nucleotide level, such as change in free energy of messenger RNA (mRNA) and the change in codon usage frequency as a result of mutation.…”

Section: Introductionmentioning

confidence: 99%

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A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

Hamasaki-Katagiri

Salari

et al. 2013

Journal of Molecular Biology

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A fundamental goal of medical genetics is the accurate prediction of genotype–phenotype correlations. As an approach to develop more accurate in silico tools for prediction of disease-causing mutations of structural proteins, we present a gene- and disease-specific prediction tool based on a large systematic analysis of missense mutations from hemophilia A (HA) patients. Our HA-specific prediction tool, HApredictor, showed disease prediction accuracy comparable to other publicly available prediction software. In contrast to those methods, its performance is not limited to non-synonymous mutations. Given the role of synonymous mutations in disease and drug codon optimization, we propose that utilizing a gene- and disease-specific method can be highly useful to make functional predictions possible even for synonymous mutations. Incorporating computational metrics at both nucleotide and amino acid levels along with multiple protein sequence/structure alignment significantly improved the predictive performance of our tool. HApredictor is freely available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Przytycka/HA_Predict/index.htm.

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Section: Discussionmentioning

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

Hamasaki-Katagiri

Salari

et al. 2013

Journal of Molecular Biology

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“…These changes are not caused by a change in mRNA integrity, but rather originate from a change in the efficiency of mutant mRNA translation. Whereas numerous non-synonymous mutations in the F9 gene have been linked to haemophilia B,31 this report provides insight into the mechanism(s) by which a single synonymous mutation can sufficiently disrupt the protein properties to cause the clinical manifestation of a bleeding disorder (figure 5). Early studies that explored the underpinnings of synonymous mutation-mediated effects on protein function4 focused on single unique mechanisms.…”

Section: Discussionmentioning

confidence: 90%

Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B

et al. 2016

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Background: Hemophilia B is caused by genetic aberrations in the F9 gene. The majority of these are non-synonymous mutations that alter the primary structure of blood coagulation Factor IX (FIX). However, a synonymous mutation c.459G>A (Val107Val) was clinically reported to result in mild hemophilia B (FIX coagulant activity 15–20% of normal). The F9 mRNA of these patients showed no skipping or retention of introns and/or change in mRNA levels, suggesting that mRNA integrity does not contribute to the origin of the disease in affected individuals. The aim of this study is to elucidate the molecular mechanisms that can explain disease manifestations in patients with this synonymous mutation. Methods: We analyze the molecular mechanisms underlying the FIX deficiency through in silico analysis and reproducing the c.459G>A (Val107Val) mutation in stable cell lines. Conformation and non-conformation sensitive antibodies, limited trypsin digestion, activity assays for FIX, interaction with other proteins, and post-translation modifications were used to evaluate the biophysical and biochemical consequences of the synonymous mutation. Results: The Val107Val synonymous mutation in F9 was found to significantly diminish FIX expression. Our results suggest that this mutation slows FIX translation and affects its conformation resulting in decreased extracellular protein level. The altered conformation did not change the specific activity of the mutated protein. Conclusions: The pathogenic basis for one synonymous mutation (Val107Val) in the F9 gene associated with hemophilia B was determined. A mechanistic understanding of these synonymous variants yields potential for guiding and developing future therapeutic treatments.

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“…Overall 21 published studies (60.0%) were related to FIX, of which 17 (48.6%) were on safety, efficacy and/or pharmacokinetics of different FIX products , two studies on dosing , one on allergic reactions and one on use of FIX worldwide . HB was the focus of seven studies, of which three studies compared features of HA or FVII deficiency to HB, two studies on correlation between genotype and phenotype of HB , one registry on incidence of inhibitors, allergic and anaphylactic reactions and one study on the global prevalence of HB . Two publications concerned one single study on gene therapy for HB .…”

Section: Resultsmentioning

confidence: 99%

Research in haemophilia B – approaching the request for high evidence levels in a rare disease

et al. 2014

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Payers in European countries request studies with high levels of evidence for decision making also for rare diseases like haemophilia B (HB). The objective of the study was to determine the status quo of current studies in HB regarding the overall level of evidence generated. The methods used for performing the study were systematic literature research in EMBASE and MEDLINE, search terms 'HB' and 'factor IX' (FIX). The inclusion criteria were journal articles (JA), conference abstracts (CA), English language, published between January 2009 and March 2013, studies only; screening of titles, abstracts, full texts subsequently. ClinicalTrials.gov search: unpublished registered trials (RT) concerning HB or FIX. The analysis was performed on research topic, sponsor, recruitment status and study design. Screening of 1639 hits yielded 31 JA describing 35 studies, and 62 CA. FIX was subject of 21 studies (60.0%) and 29 CA (46.8%). Seven studies focused on various aspects of HB, six on haemophilia studies with separate HB data. Screening of 173 hits from ClinicalTrials.gov yielded 42 RT. Overall, 32 RT (76.2%) related to FIX. Measurement of health-related quality of life (HRQoL) was identified in none of these studies, four CA (6.5%), four RT (9.5%). Randomized study design was found in one study (2.9%), four RT (9.5%). Three studies (8.6%) and seven RT (16.7%) were prospective, observational and comparative. The majority of published clinical studies do not meet payers' expectations for evidence. Therefore, clinical investigation concepts addressing randomization, outcomes research including HRQoL and comparison of therapy options should be discussed. Refined statistical methods and exploitation of complementary real-life data sources may fill current evidence gaps concerning rare diseases.

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Analysis of F9 point mutations and their correlation to severity of haemophilia B disease

Cited by 12 publications

References 19 publications

A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B

Research in haemophilia B – approaching the request for high evidence levels in a rare disease

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