Mutations associated with hemophilia B in Turkish patients

Çağlayan, S. Hande; Gökmen, Yunus; Aktuğlu, Gülten; Gürgey, Aytemiz; Sommer, Steve S.

doi:10.1002/(sici)1098-1004(1997)10:1<76::aid-humu11>3.0.co;2-x

Cited by 6 publications

(4 citation statements)

References 20 publications

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“…We found that the HDHB residues are mainly part of alpha helices or beta-strands, are connected to 12–14 other residues via non-covalent or hydrogen bonds, are buried at the core of the Gla and the SP domains, and although mutations at these residues are mainly associated to severe forms of HB, occasionally there are reports of moderate symptoms ( Figure 2C ). Among these residues, Phe424 is located at the edge between the SP and the EGF2 domains, and is consistently associated with severe forms of HB if mutated to leucine, valine, or serine ( Chen et al, 1991 ; Caglayan et al, 1997 ; Liu et al, 2000 ). Moreover, we found that in the FIXa RIN, 40 residues take part in atomic interactions with residues from a different domain.…”

Section: Resultsmentioning

confidence: 99%

“…These residues are located mainly at the outer regions of EGF1 and EGF2 and have neighbors at different domains, most likely stabilizing the overall FIXa conformation. Most mutations at these residues are associated to severe forms of HB (e.g., Gly125Arg ( Caglayan et al, 1997 ); however, residues Ser107, Lys109, and Asp111 had no reports of HB, possibly because these mutations occur in humans but people carrying this mutation did not show symptoms, given that these amino acid positions are not conserved and accepted different types of amino acids throughout evolution ( Supplementary Table S1 ).…”

Section: Resultsmentioning

confidence: 99%

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A Machine Learning Framework Predicts the Clinical Severity of Hemophilia B Caused by Point-Mutations

2022

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Blood coagulation is a vital physiological mechanism to stop blood loss following an injury to a blood vessel. This process starts immediately upon damage to the endothelium lining a blood vessel, and results in the formation of a platelet plug that closes the site of injury. In this repair operation, an essential component is the coagulation factor IX (FIX), a serine protease encoded by the F9 gene and whose deficiency causes hemophilia B. If not treated by prophylaxis or gene therapy, patients with this condition are at risk of life-threatening bleeding episodes. In this sense, a deep understanding of the FIX protein and its activated form (FIXa) is essential to develop efficient therapeutics. In this study, we used well-studied structural analysis techniques to create a residue interaction network of the FIXa protein. Here, the nodes are the amino acids of FIXa, and two nodes are connected by an edge if the two residues are in close proximity in the FIXa 3D structure. This representation accurately captured fundamental properties of each amino acid of the FIXa structure, as we found by validating our findings against hundreds of clinical reports about the severity of HB. Finally, we established a machine learning framework named HemB-Class to predict the effect of mutations of all FIXa residues to all other amino acids and used it to disambiguate several conflicting medical reports. Together, these methods provide a comprehensive map of the FIXa protein architecture and establish a robust platform for the rational design of FIX therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Machine Learning Framework Predicts the Clinical Severity of Hemophilia B Caused by Point-Mutations

2022

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“…The molecular pro le of patients with HB varies widely among different studies [24][25][26][27][28][29][30][31]. According to a population-based study from Sweden, Val107silent, Arg145His, and Ala233Thr mutations are commonly found in mild HB cases, followed by Arg-4Trp in moderate cases and Arg248stop, Arg29stop, and Arg252stop in severe cases [24].…”

Section: Discussionmentioning

confidence: 99%

Genotype-phenotype analyses of Iranian patients with and without hemophilia B Leyden: A single-center study

Moghadam,

Manafzadeh,

Dajliry

et al. 2024

Preprint

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Background There is a high prevalence of inherited bleeding disorders in Iran, such as hemophilia A (HA) and hemophilia B (HB). This study aimed to analyze the molecular and clinical profiles of patients with HB.Methods A single-center study was conducted among patients with severe HB between March 20, 2000, and June 31, 2023. The polymerase chain reaction (PCR) amplification was used for all of the major regions, such as the promoter, the exons, the adjacent intronic regions, and the untranslated regions of the F9 gene. Finally, Sanger sequencing was performed on the PCR products.Results A total of 111 HB patients (17 with HB Leyden and 94 without HB Leyden) were enrolled in this study. The median age of the patients at the time of diagnosis was 12 months (IQR: 6 months to 60 months). A family history of hemophilia was reported in 64 (57.7%) of patients. The most common bleeding manifestations were hemarthrosis, bruising, and oral cavity bleeding. Among 94 patients without HB Leyden, 59 (62.8%) had missense, 21 (22.3%) had nonsense, and 8 (8.5%) had frameshift mutations. Moreover, the most frequent mutation in HB Leyden was c.-17 A > G in this study. Finally, two novel mutations (c. -14 T > C and c. -56 T > A) were identified in the promotor region.Conclusion The results of this study confirm that HB is caused by a wide range of molecular defects in Iran. Thus, by knowing the genotypes and phenotypes, we would be able to stratify the patients which is important in terms of their management and outcome.

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“…The number of haemophilia B patients in Turkey is thought to be about 1000. To date, nine point mutations and one large deletion in 10 Turkish haemophilia B patients have been identified (Çağlayan et al , 1997). In order to reveal new mutations and obtain a more comprehensive analysis of the molecular pathology of haemophilia B in Turkey, a larger group of patients were included in this study.…”

Section: Summary Of the Clinical And Sequence Datamentioning

confidence: 99%

Molecular pathology of haemophilia B in Turkish patients: identification of a large deletion and 33 independent point mutations

et al. 2003

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Summary. Heterogeneous mutations in the coagulation factor IX (FIX) gene result in a bleeding tendency known as haemophilia B. The haemophilia B mutation database has a total of 2353 patient entries, including 10 of the estimated 1000 Turkish patients. In this study, a more comprehensive analysis of the molecular pathology of haemophilia B in Turkey revealed one large deletion and 33 point mutations in the FIX gene of 34 unrelated patients. Haplotype analysis using six polymorphic sites showed that the mutations identified in a total of 45 patients occurred on 13 different haplotypes and that each mutation was family specific.

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Mutations associated with hemophilia B in Turkish patients

Cited by 6 publications

References 20 publications

A Machine Learning Framework Predicts the Clinical Severity of Hemophilia B Caused by Point-Mutations

A Machine Learning Framework Predicts the Clinical Severity of Hemophilia B Caused by Point-Mutations

Genotype-phenotype analyses of Iranian patients with and without hemophilia B Leyden: A single-center study

Molecular pathology of haemophilia B in Turkish patients: identification of a large deletion and 33 independent point mutations

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