FGG Gene Research Articles

Clinical phenotypes and genotypes of congenital fibrinogen disorder: an analysis of 16 children

To investigate the clinical phenotypes and genotypes of children with congenital fibrinogen disorder (CFD). A retrospective analysis was conducted on the clinical data of 16 children with CFD. Polymerase chain reaction was used to amplify all exons and flanking sequences of the FGA, FGB, and FGG genes, and sequencing was performed to analyze mutation characteristics. Among the 16 children, there were 9 boys (56%) and 7 girls (44%), with a median age of 4 years at the time of attending the hospital. Among these children, 9 (56%) attended the hospital due to bleeding events, and 7 (44%) were diagnosed based on preoperative examination. The children with bleeding events had a significantly lower fibrinogen activity than those without bleeding events (P<0.05). Genetic testing was conducted on 12 children and revealed a total of 12 mutations, among which there were 4 novel mutations, i.e., c.80T>C and c.1368delC in the FGA gene and c.1007T>A and C.1053C>A in the FGG gene. There were 2 cases of congenital afibrinogenemia caused by null mutations of the FGA gene, with relatively severe bleeding symptoms. There were 7 cases of congenital dysfibrinogenemia mainly caused by heterozygous missense mutations of the FGG and FGA genes, and their clinical phenotypes ranged from asymptomatic phenotype to varying degrees of bleeding. The clinical phenotypes of children with CFD are heterogeneous, and the severity of bleeding is associated with the level of fibrinogen activity, but there is a weak association between clinical phenotype and genotype.

Dysfibrinogenemia and hypofibrinogenemia - Spectrum of pathogenic variants in Slovak patients.

Congenital hypofibrinogenemia (CH) and congenital dysfibrinogenemia (CD) are rare coagulation disorders caused by quantitative or qualitative defects in the fibrinogen gene. The aim of this study was to characterize the genetic background and the clinical manifestations of congenital fibrinogen disorders in the patients from Slovakia registered at the National Haemophilia Centre. Results of genetic analysis of the fibrinogen genes FGA, FGB and FGG using polymerase chain reaction followed by direct sequencing were evaluated in 36 patients. Molecular-genetic analysis revealed six novel variants - FGA c.923_968dup p.(Gly324Lysfs*44) and FGG c.1105C>T p.(His369Tyr) were identified in CD patients. In CH patients, in the FGG gene c.8G>A p.(Trp3*), c.823G>T p.(Glu275*) and c.323C>A p.(Ala108Asp) variants were detected. In the FGB gene c.1427C>T p.(Ser476Leu) was identified. This study is a positive contribution towards expanding knowledge about genetic variants in patients with congenital fibrinogen disorders.

Exploring the interplay of MTHFR and FGG polymorphisms with serum levels of adiponectin and leptin in pediatric lupus nephritis: a pilot study

BackgroundAdiponectin and leptin are pivotal in the regulation of metabolism. Pediatric lupus nephritis (pLN), a manifestation of childhood systemic lupus erythematosus (SLE) affecting the kidneys, is associated with impaired adipokine levels, suggesting a role in pLN pathogenesis. The aim of this study was to explore the potential relationship between specific single-nucleotide polymorphisms (SNPs)—methylenetetrahydrofolate reductase (MTHFR) rs1801131 and fibrinogen gamma chain (FGG) rs2066865—and the serum levels of leptin and adiponectin in patients with pLN.MethodsNinety-eight pLN patients and one hundred controls were enrolled in the study. Serum leptin and adiponectin levels were measured using ELISA. DNA extraction and real-time PCR genotyping were performed for MTHFR rs1801131 and FGG rs2066865 SNPs.ResultsCompared to healthy controls, pLN patients exhibited significantly greater serum leptin (11.3 vs. 18.2 ng/mL, p < 0.001) and adiponectin (18.2 vs. 2.7 ug/mL, p < 0.001). Adiponectin levels were positively correlated with proteinuria (p < 0.05), while leptin levels positively correlated with proteinuria, SLE disease activity index-2000 (SLEDAI-2K), and cyclophosphamide usage (all p < 0.05). There was no significant association between MTHFR rs1801131 or FGG rs2066865 SNPs and pLN in either codominant or allelic models (all p > 0.05). However, the AG genotype of FGG gene rs2066865 SNP was significantly associated with high leptin levels (> 15 ng/mL) (p = 0.01).ConclusionSerum adiponectin and leptin levels are associated with pathological manifestations of pLN. High leptin levels are associated with the AG genotype of FGG rs2066865 SNP in pLN patients, suggesting direct involvement in disease progression and potential utility as a disease biomarker.

АССОЦИАЦИЯ ПОЛИМОРФИЗМА ГЕНОВ СИСТЕМЫ ГЕМОСТАЗА С КЛИНИКО-ЛАБОРАТОРНЫМИ ПОКАЗАТЕЛЯМИ У ПАЦИЕНТОВ С ИНФАРКТОМ МИОКАРДА

The article presents the analysis of the association between polymorphic variants of the FGA, FGG, F2, F5, F11, F13, PAI-1, and GP6 genes and clinical, instrumental, and laboratory data in patients with myocardial infarction from the Republic of Belarus. It has been demonstrated that in patients with myocardial infarction, there exist statistically significant correlations between polymorphic variants of the genes F11 (rs2289252 and rs2036914), F13 (rs5985), F5 (rs6025), PAI-1 (rs1799889), FGG (rs2066865), and a variety of laboratory values and functional indicators of the myocardium. A comprehensive analysis of the genetic component (DNA polymorphism) and the outcomes of dynamic follow-up of the patient in hospital enable clinicians to accurately assess potential hazards of the occurrence and unfavorable progression of a number of diseases including myocardial infarction.

Evaluation of Innovative Laboratory Tests to Predict a Thrombotic Phenotype in a Family with Dysfibrinogenemia and a Novel FGG Mutation

Background: Hypodysfibrinogenemia is a rare hereditary fibrinogen disorder characterized by quantitative and qualitative fibrinogen defects. These fibrinogen defects can cause thrombotic and hemorrhagic phenotypes. Unfortunately, predicting the phenotype in a specific patient is often not possible with routine coagulation tests. Aims: To characterize the phenotype and the genetic profile of a family with hypodysfibrinogenemia and to investigate the ability of innovative tests to predict bleeding and/or thrombotic phenotypes in asymptomatic family members. Methods: The proband, a 60-year-old woman with both bleeding and thrombotic complications who is currently on DOAC treatment, and two daughters were referred to our Hemophilia Treatment Center (HTC) for phenotypical and genotypical analysis of a congenital fibrinogen disorder (CFD). Extensive laboratory testing was done, as well as DNA-sequence analysis and molecular modelling. Thrombin generation and microfluidic testing were also performed to investigate their ability in phenotype prediction. Results: Fibrinogen activity and antigen levels led to the diagnosis of dysfibrinogenemia in the proband and hypodysfibrinogenemia in both daughters. In all three cases, the same heterozygous missense mutation in the FGG gene was uncovered. This likely pathogenic mutation leads to the p.(Tyr375Cys) amino acid change. Molecular modeling predicted possible conformational changes or covalent dimerization of the fibrinogen molecule. Thrombin generation was elevated in one daughter. Microfluidic testing showed enhanced fibrin formation in both daughters, regardless of the coagulation trigger. Conclusion: We described a family with hypodysfibrinogenemia in whom a novel heterozygous missense mutation in the FGG gene was found, possibly leading to conformational changes or covalent dimerization of the fibrinogen molecule. Furthermore we showed that microfluidic testing and thrombin generation can indicate a thrombotic phenotype in these patients, not detected with routine coagulation tests.

Genetic analysis of a Chinese pedigree affected with Congenital dysfibrinogenemia due to variant of FGG gene

To explore the coagulation deficit and genetic basis for a Chinese pedigree affected with Congenital dysfibrinogenemia (CD). Peripheral venous blood samples of the proband and her family members (including 4 individuals from three generations) were subjected to routine blood test and assays of liver and kidney functions and viral hepatitis to exclude related diseases. Clauss method and DFg-PT method were used to determine the fibrinogen activity (Fg:C), and an immunoturbidimetric assay was used to determine the level of fibrinogen antigen (Fg:Ag). All of the exons (22 in total) and their flanking sequences of the FGA, FGB and FGG genes were amplified by PCR and directly sequenced. Variants in the coding regions of the three genes and transcriptional splicing sites were screened by using Mutation SurveyorTM software. The Clauss method showed that Fg:C was significantly reduced in the proband and her father, whilst her mother and son were normal. With the DFg-PT method, the proband, her parents and son were all within the normal range. The Fg:C/Fg:Ag ratio of the proband and her father was lower than 0.7, whilst her mother and son were above 0.7. No significant change in the prothrombin time, activated partial thromboplastin clotting time and thrombin time was noted. Two genetic variants were detected, which included a homozygous missense variant in the FGA gene [c.991A>G (p.Thr331Ala)], which was predicted to be benign, and a heterozygous missense variant of the γ chain of the FGG gene [c.1211C>G (p.Ser404Phe)], which is located in a conserved region and unreported in the CLINVAR/HGMD/EXAC/1000G databases and literature. This pedigree has conformed to the autosomal dominant inheritance of CD. The c.1211C>T (p.Ser404Phe) missense variant of the γ chain of the FGG gene probably underlay the pathogenesis of CD in this pedigree. The variant was unreported previously and named as "Fibrinogen Harbin II Ser404Phe".

MP01-02 PROTEOMIC ANALYSIS OF SEMINAL FLUID IN RHESUS MACAQUES EXPOSED TO DELTA-9-TETRAHYDROCANNABINOL

You have accessJournal of UrologyCME1 Apr 2023MP01-02 PROTEOMIC ANALYSIS OF SEMINAL FLUID IN RHESUS MACAQUES EXPOSED TO DELTA-9-TETRAHYDROCANNABINOL Jasper C. Bash, Lyndsey E. Shorey-Kendrick, Carol B. Hannah, Charles A. Easley, Eliot Spindel, Jamie O. Lo, and Jason C. Hedges Jasper C. BashJasper C. Bash More articles by this author , Lyndsey E. Shorey-KendrickLyndsey E. Shorey-Kendrick More articles by this author , Carol B. HannahCarol B. Hannah More articles by this author , Charles A. EasleyCharles A. Easley More articles by this author , Eliot SpindelEliot Spindel More articles by this author , Jamie O. LoJamie O. Lo More articles by this author , and Jason C. HedgesJason C. Hedges More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003212.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cannabis use has been associated with male infertility, but the etiology is not well understood. Seminal fluid is comprised of multiple factors (e.g. proteins), that influence fertility. Our objective was to determine the impact of chronic delta-9-tetrahydrocannabinol (THC) use on the seminal fluid proteome in a rhesus macaque (RM) model. METHODS: 6 adult RMs were given a daily THC edible over 280 days (∼4 spermatogenesis cycles) with serial non-sedated semen collection. Differential expression of proteins in the seminal fluid at baseline (pre-THC), high-THC dose (2.5 mg/7 kg/day), and post-THC discontinuation for 140 days (∼2 spermatogenesis cycles) was evaluated. Proteomic analysis was performed by liquid chromatography tandem mass spectrometry followed by statistical analysis to identify differentially expressed proteins. RESULTS: Proteomic analysis resulted in 1,395 quantifiable proteins (Figure 1A). The average percent identity was 88.6% (SD=14.9%). All RM proteins were matched to human proteins with 99.4% of the RM proteins (1,386) exceeding an identity cutoff of 44.3% (average minus 3 SDs). 7 proteins reached FDR significance in any contrast, thus we focused downstream analyses on nominally significant candidate proteins. Ingenuity Pathway Analysis (Figure 1B) revealed that high-THC exposure was associated with dysregulation of pathways related to “Remodeling of Epithelial Adherens Junctions”, “Axonal Guidance Signaling”, and “Glucocorticoid Receptor Signaling”. THC discontinuation for 140 days was associated with decreased “LXR/RXR Activation”, “Acute Phase Response Signaling”, and “Production of Nitric Oxide and ROS in Macrophages”. 5 proteins dysregulated with THC and significantly restored to baseline included products of CHIT1, FGG, MMP9, TGFBI, and CFB genes (Figure 1D). CHIT1 has been associated with oligozoospermia and MMP9 protein with sperm motility. CONCLUSIONS: This study demonstrated the translational strength of the RM model to study male reproductive health; there was significant seminal fluid proteome homology between humans and RMs. THC-exposed RMs are likely to exhibit proteins in their seminal ejaculate that are involved in regulatory processes that could potentially contribute to male infertility. Source of Funding: OHSU Faculty SEED Award and ASRM Pilot and Exploratory Grant © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jasper C. Bash More articles by this author Lyndsey E. Shorey-Kendrick More articles by this author Carol B. Hannah More articles by this author Charles A. Easley More articles by this author Eliot Spindel More articles by this author Jamie O. Lo More articles by this author Jason C. Hedges More articles by this author Expand All Advertisement PDF downloadLoading ...

Genetic analysis of two Chinese pedigrees affected with Hereditary hypofibrinemia due to missense variants

To retrospectively analyze the clinical phenotypes and genetic variants in two Chinese pedigrees affected with Hereditary hypofibrinemia (IFD) and explore their molecular pathogenesis. Two probands and their pedigree members were admitted to the First Affiliated Hospital of Wenzhou Medical University on March 30, 2021 and May 27, 2021, respectively. Clinical phenotypes of the probands were collected, and blood clotting indexes of the probands and their pedigree members were determined. Variants of the FGA, FGB and FGG genes were analyzed by Sanger sequencing, and candidate variants were verified by sequence comparison. Bioinformatic software was used to analyze the conservation of the amino acids and pathogenicity of the proteins. Alteration in protein structure and intermolecular force before and after the variant was analyzed by simulating the protein model. Proband 1, a 18-year-old male, had significantly low plasma fibrinogen activity (Fg:C) and plasma fibrinogen antigen (Fg:Ag), respectively at 0.80 g/L and 1.00 g/L. Proband 2, a 43-year-old male, had slightly low Fg:C and Fg:Ag at 1.35 g/L and 1.30 g/L, respectively. The Fg:C and Fg:Ag of proband 1's father, proband 2's father and son were also below the normal level. Genetic testing showed that proband 1 had harbored a heterozygous missense variant of c.688T>G (p.Phe230Val) in exon 7 of the FGG gene, which was inherited from his father. Proband 2, his father and son all had harbored a heterozygous variant of c.2516A>C (p.Asn839Thr) in exon 6 of the FGA gene. Homology analysis showed that the Phe230 and Asn839 residues were highly conserved among homologous species. Bioinformatic analysis predicted that both p.Phe230Val and p.Asn839Thr were pathogenic variants. Analysis of protein simulation model showed that the p.Asn839Thr variant has changed the hydrogen bo`nd between the amino acids, thus affecting the stability of the protein structure. The heterozygous missense variants of p.Phe230Val and p.Asn839Thr probably underlay the IFD in the two pedigrees.

Fibrinogen Deficiency with Thrombotic Manifestations.

Fibrinogen deficiencies are very rare. Qualitative fibrinogen deficiencies (dysfibrinogenaemia and hypodysfibrinogenemia) are functional disorders that can present with both haemorrhagic symptoms and with thrombotic phenomena as unique and paradoxical manifestation. We present the case of a 77-year-old man being investigated for a partially thrombosed abdominal aortic aneurysm as well as an ischaemic stroke 20 years previously. Basic coagulation tests were normal but extended tests revealed a lengthened thrombin time (TT) combined with a significant drop in fibrinogen concentration measured with the Clauss assay and by nephelometry. After secondary fibrinogen deficiencies were ruled out, a heterozygous variant in the FGG gene was detected by next-generation sequencing, and congenital hypodysfibrinogenemia was diagnosed. Acenocumarol was initiated and no new thrombotic or haemorrhagic events had occurred after a year of follow-up.In almost 25% of cases, thrombotic events may be the only clinical manifestation of functional fibrinogen deficiencies. They are a rare cause of thrombophilia, and are probably underdiagnosed due to normal standard coagulation test results as well as a possible absence of haemorrhagic events. Consequently, a TT test (an initial ‘rule out’ test) should be requested in order to promptly identify these patients. Moreover, discrepancies in derived and Clauss fibrinogen test results should suggest a functional disorder. Finally, new coagulation techniques based on the functional characterization of clot formation, such as ROTEM or thrombin generation assay, could help characterize these entities and suggest new therapeutic approaches.LEARNING POINTSFunctional fibrinogen deficiencies can present with thrombotic manifestations only, and are a rare and probably underdiagnosed cause of thrombophilia.Thrombin time is a highly sensitive test to rule out other conditions as aPTT and PT results may be within normal ranges, especially in functional deficiencies.Discrepancies between derived and Clauss fibrinogen findings, fibrinogen protein measurements and the use of new techniques (ROTEM or thrombin generation) are important for correct approach.

Fibrinogen gamma-chain mutation, p.Ile171His, leads to hereditary hypofibrinogenemia

Objective: To explore the clinical phenotype and genotype of a family with hereditary hypofibrinogenemia. Methods: Activated partial thrombin time (APTT), prothrombin time (PT),thrombin time (TT) and thrombelastogram (TEG) were tested in all family members. Fibrinogen activity and antigen were detected by Clauss method and immunoturbidimetric method respectively. All exons and flanking sequences of fibrinogen FGA,FGB,FGG genes were analyzed by PCR, and the products were subjected to Sanger sequencing. Results: The proband represented prolonged PT and TT, low Fg activity and antigen, elevated K value and decreased Angle value in TEG. Other family members reported similar changes including proband's father,daughter and son, and his elder brother and his niece. Exon 5 c.510_512 of FGG gene in the proband revealed a minor deletion mutation. Conclusion: The novel heterozygous missense mutation of exon 5 c.510_512del (Gln170_Ile171 del ins His) of FGG gene is the molecular mechanism that leads to hereditary hypofibrinogenemia in this family.

Variants of MTHFR and FGG Genes Are Associated with Levels of Leptin but Not Adiponectin in Colombian Pediatric Lupus Nephritis

Variants of MTHFR and FGG Genes Are Associated with Levels of Leptin but Not Adiponectin in Colombian Pediatric Lupus Nephritis

Clinical and molecular characterization of Iranian patients with congenital fibrinogen disorders

IntroductionCongenital fibrinogen disorders (CFDs) are caused by mutations in the FGA, FGB and FGG genes and are classified as quantitative and qualitative fibrinogen defects. This study sought to determine the genetic background of CFDs in Iran and to examine the genotype-phenotype correlation. MethodsFourteen patients with a CFD diagnosis were included. Fibrinogen antigen and activity were measured by the immunoturbidimetric and Clauss methods respectively. Gene sequencing was performed following a polymerase chain reaction amplification of fibrinogen’s genes. The ISTH Bleeding Assessment Tool was also evaluated for all cases. ResultsPatients were diagnosed with dysfibrinogenemia (n = 10), hypodysfibrinogenemia (n = 2) and afibrinogenemia (n = 2). Seven different mutations located on FGA exon 2 (57 %), exon 4 (7%), exon 5 (7%) and FGG exon 8 (29 %) were identified. In patients with qualitative deficiencies, mutations were including p.Arg38Thr, p.Arg35His, p.Arg35Cys, p.Val145Asp, and p.Arg301Cys and were including p.Gly316GlufsX105 and p.Trp52stop in afibrinogenemic patients. In dysfibrinogenemia, two hotspot mutations, FGA Arg35 and FGG Arg301 were identified in 60 % of patients and the remaining (40 %) had p.Arg38Thr mutation. The p.Val145Asp and two hotspot mutations, p.Arg35His, p.Arg35Cys, were identified for the first time in Iran. The overall median (range) bleeding score (BS) was 4 (0-6) in all patients and it was 3.5 (0–5) in dysfibrinogenemia. Cutaneous bleeding and menorrhagia were the most common bleeding manifestations. ConclusionThere was a weak genotype-phenotype correlation in CFDs and patients with dysfibrinogenemia were more symptomatic than in previous studies. Despite ethnic’s differences, the prevalence of hotspot mutations in dysfibrinogenemia was similar to the other studies.

Identification of a novel mutation in congenital afibrinogenemia in Iranian patients.

Congenital afibrinogenemia is a rare autosomal recessive disorder that is caused by defects in the fibrinogen. Fibrinogen is a hexameric glycoprotein made of two pairs of three homologous polypeptide chains including Aα, Bβ, and γ that are encoded by three genes named FGA, FGB, and FGG. We aim to study four Iranian families who were referred to our lab for molecular diagnosis of afibrinogenemia. Genomic DNA was extracted from whole blood and Sanger sequencing was performed using primers for all exons and exon-intron junctions of FGA, FGB, and FGG genes. Pathogenicity of the variants was predicted using different in-silico tools and was interpreted according to the American College of Medical Genetics and Genomics guideline. We found three types of mutations in the studied families; two were in the FGA gene and one was in the FGB gene including a nonsense, a novel splicing mutation, and two deletion ones. The nonsense and the deletion mutations may cause a truncated protein and are likely pathogenic and pathogenic, respectively. The novel mutation of splicing found in the FGB gene is a pathogenic one and can break the wild-type acceptor site. Studying mutations in afibrinogenemia patients can expand our knowledge about this disease in Iran.

Congenital Fibrinogen Deficiency Caused by Novel FGG Gene Mutation

To detect and analyze coagulation related indexes and genotypes of a patient with congenital fibrinogen deficiency and his family members, and to investigate the possible molecular pathogenesis. Four peripheral blood samples (proband and 3 family members) were collected and the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg), D-Dimer and eight coagulation factor indicators were detected. All exons and flanking sequences of the FGA, FGB, and FGG genes encoding the three peptide chains of fibrinogen were sequenced and analyzed by bioinformatics. Among the eight coagulation factors of the proband and the elder sister, F Ⅴ and F Ⅷ were slightly higher, TT was significantly prolonged, and Fg was significantly reduced. Sequencing results showed that c.901C>T heterozygous mutation existed in the FGG gene. Bioinformatics analysis showed that the mutation changed the original protein structure and reduced the number of hydrogen bonds. The fibrinogen gamma chain c.901C>T heterozygous mutation is the main cause of congenital fibrinogen deficiency in this family. This mutation is reported for the first time at home and abroad.

A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype.

Congenital hypofibrinogenemia is a rare bleeding disorder characterized by a proportional decrease of functional and antigenic fibrinogen levels. Hypofibrinogenemia can be considered the phenotypic expression of heterozygous loss of function mutations occurring within one of the three fibrinogen genes (FGA, FGB, and FGG). Clinical manifestations are highly variable; most patients are usually asymptomatic, but may appear with mild to severe bleeding or thrombotic complications. We have sequenced all exons of the FGA, FGB, and FGG genes using the DNA isolated from the peripheral blood in two unrelated probands with mild hypofibrinogenemia. Coagulation screening, global hemostasis, and functional analysis tests were performed. Molecular modeling was used to predict the defect of synthesis and structural changes of the identified mutation. DNA sequencing revealed a novel heterozygous variant c.1421G>A in exon 8 of the FGB gene encoding a Bβ chain (p.Trp474Ter) in both patients. Clinical data from patients showed bleeding episodes. Protein modelling confirmed changes in the secondary structure of the molecule, with the loss of three β sheet arrangements. As expected by the low fibrinogen levels, turbidity analyses showed a reduced fibrin polymerisation and imaging difference in thickness fibrin fibers. We have to emphasize that our patients have a quantitative fibrinogen disorder; therefore, the reduced function is due to the reduced concentration of fibrinogen, since the Bβ chains carrying the mutation predicted to be retained inside the cell. The study of fibrinogen molecules using protein modelling may help us to understand causality and effect of novel genetic mutations.

Hereditary Hypofibrinogenemia with Hepatic Storage.

Fibrinogen is a 340-kDa plasma glycoprotein constituted by two sets of symmetrical trimers, each formed by the Aα, Bβ, and γ chains (respectively coded by the FGA, FGB, and FGG genes). Quantitative fibrinogen deficiencies (hypofibrinogenemia, afibrinogenemia) are rare congenital disorders characterized by low or unmeasurable plasma fibrinogen antigen levels. Their genetic basis is represented by mutations within the fibrinogen genes. To date, only eight mutations, all affecting a small region of the fibrinogen γ chain, have been reported to cause hereditary hypofibrinogenemia with hepatic storage (HHHS), a disorder characterized by protein aggregation in the endoplasmic reticulum, hypofibrinogenemia, and liver disease of variable severity. Here, we will briefly review the clinic characteristics of HHHS patients and the histological feature of their hepatic inclusions, and we will focus on the molecular genetic basis of this peculiar type of coagulopathy.

Редкий случай гиподисфибриногенемии у пациента без гематомезенхимальной дисплазии

Фибриноген и коллаген являются важнейшими протеинами межклеточного матрикса, оказывающие прямое влияние как на дифференцировку мезенхимальных стволовых клеток, так и на остеогенез. Кроме того, в клинической практике встречаются случаи протекания данного синдрома не в классическом виде, которые требуют более углубленного изучения звеньев патогенеза и разработки оптимальной коррекции заболевания. Нами проведен поиск литературных данных по ключевым словам в базах данных PubMed, UpToDate, BMJ. Представлен обзор современных научных данных и результаты наблюдения редкого клинического случая у пациента с гиподисфибриногенемией с проявлениями асептического некроза головок бедренных костей без гематомезенхимальной дисплазии. Заключение: В целом, в настоящее время подробно изучены различные аспекты клинико-биохимического патогенеза аномалий фибриногена, но остаются «белые пятна» в изучении тонких патогенетических механизмов на молекулярно-генетическом уровне, а именно: катаболизм белка, реакции раздельного синтеза отдельных полипептидных цепей фибриногена в разных тканях. Остается нерешенным вопрос о целесообразности применения корригирующих гемостаз препаратов таргетного действия при отсутствии у пациента выраженных тромботических и геморрагических проявлений. Fibrinogen and collagen are the most important intercellular matrix proteins that directly effect on the differentiation of mesenchymal stem cells and osteogenesis. In addition, there are non-classical cases of this syndrome that require indepth study of pathogenesis and optimal disease correction. We examined literature data by keywords in databases PubMed, UpToDate, BMJ. We presented a review of current scientific data and observation results of a rare clinical case in a patient with hypodysfibrinogenemia without hematomesenchymal dysplasia with manifestations of aseptic necrosis of femoral heads. Conclusions: In general, various aspects of clinical and biochemical pathogenesis of fibrinogen abnormalities are currently studied in detail, but there are “white spots” in the study of sophisticated pathogenetic mechanisms at the molecular genetic level, namely protein catabolism, the reaction of separate synthesis of individual fibrinogen polypeptide chains in different tissues. Unresolved is the question of applicability of hemostatic corrective drugs in the absence of expressed thrombotic and hemorrhagic manifestations.

Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype

Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of fibrinogen to insoluble polymer fibrin gives structural stability, strength, and adhesive surfaces for growing blood clots. Equally important, the exposure of its non-substrate thrombin-binding sites after fibrin clot formation promotes antithrombotic properties. Fibrinogen and fibrin have a major role in multiple biological processes in addition to hemostasis and thrombosis, i.e., fibrinolysis (during which the fibrin clot is broken down), matrix physiology (by interacting with factor XIII, plasminogen, vitronectin, and fibronectin), wound healing, inflammation, infection, cell interaction, angiogenesis, tumour growth, and metastasis. Congenital fibrinogen deficiencies are rare bleeding disorders, characterized by extensive genetic heterogeneity in all the three genes: FGA, FGB, and FGG (enconding the Aα, Bβ, and γ chain, respectively). Depending on the type and site of mutations, congenital defects of fibrinogen can result in variable clinical manifestations, which range from asymptomatic conditions to the life-threatening bleeds or even thromboembolic events. In this manuscript, we will briefly review the main pathogenic mechanisms and risk factors leading to thrombosis, and we will specifically focus on molecular mechanisms associated with mutations in the C-terminal end of the beta and gamma chains, which are often responsible for cases of congenital afibrinogenemia and hypofibrinogenemia associated with thrombotic manifestations.

Evaluation of single nucleotide polymorphisms in 6 candidate genes and carotid intima-media thickness in community-dwelling residents.

Evidence suggests the existence of association between a large panel of modifiable biomarkers representing inflammation, coagulation, paraoxonase, and endothelial activation pathways and carotid atherosclerosis. Thus, this study investigated whether CRP, FGA, FGB, FGG, PON1, and EDNRA gene variants affected plasma hs-CRP, fibrinogen levels, and thickness of carotid intima media thickness (IMT). Nineteen single-nucleotide polymorphisms of CRP, FGA, FGB, FGG, PON1, and EDNRA genes were examined in 480 participants from 160 families. Carotid IMT was measured by ultrasound. Generalized linear models with generalized estimating equation were utilized to consider the dependence of subjects within families. In the recessive model, homozygotes for the minor alleles of rs1800789, rs1800790 and rs4220 SNPs in FGB gene indicated a reduced risk of IMT (Exp. β = 0.89, 0.89, 0.88), which remained significant after adjustment for confounding factors. Significant interaction effects between CRP SNP rs1130864 and rs3093059 and gender for IMT were observed with a significant association in men only. Men carrying minor-minor genotype of CRP SNP rs1130864 and rs3093059 had 0.70- and 0.78-fold lower IMT than men carrying minor-major/major-major genotype. We also observed that the interaction of CRP SNP rs1130864 and rs3093059 with obesity on IMT, hs-CRP and fibrinogen levels. These results support the hypothesis that inflammatory genes are involved in atherosclerosis, most likely via complex gene-gender and gene-obesity interactions.

One case of abnormal fibrinogenemia and literature review

Objective To explore the clinical characteristics, diagnosis and treatment of abnormal fibrinogenemia. Methods On July 30, 2018, one case of patient with abnormal fibrinogenemia who was admitted at First People′s Hospital of Zigong was selected as the research subject. The patient was female, and 52 years old. The tests of pure tone audiometry, coagulation function were performed in this patient. And FGA, FGB and FGG genes of patients were sequenced. Patient was diagnosed and treated based on her clinical manifestations, laboratory test results. Follow-up was conducted until August 2019. Retrospective analysis method was used to collect the clinical data of this patient, and to analyze her clinical manifestations, diagnosis and treatment process. In addition, China National Knowledge Infrastructure database, Wanfang Data Knowledge Service Platform, PubMed database were searched for the same case reports as the patient′s genetic mutation. The retrieval time is from the database inception to December 31, 2018. This article summarizes types of genetic mutations related to this patient with abnormal fibrinogenemia, patients′ bleeding and thrombotic symptoms, and so on. This study meets the requirements of the World Medical Association Declaration of Helsinki revised in 2013. Results ① On July 30, 2018, the patient was admitted to Department of Otorhinolaryngology of First People′s Hospital of Zigong due to left hearing loss for 1+ months . The patient complained of tinnitus, dizziness, low back pain, no oral cavity and gingival bleeding, no subcutaneous petechiae and ecchymosis, no hemoptysis, no abdominal pain and diarrhea, no black stools, etc.. The patient was in good health, and there was no history of bleeding and thrombosis in the first and second degree relatives of the family. ② After the patient was admitted, pure tone audiometry showed that moderate-severe sensorineural hearing loss of the left ear. Results of coagulation function test showed that prothrombin time (PT) was 11.3 s, activated partial thromboplastin time (APTT) was 23.4 s, thrombin time (TT) was 48.4 s, and fibrinogen value was 0.31 g/L. ③ Sequencing results of the FGA gene of this patient showed that c. 104G>A (p.Arg35His) missense mutation in exon 2 and c. 16A>G (p.Ile6Val) missense mutation in exon 1, and all were heterozygous mutations. ④ The patient was diagnosed with abnormal fibrinogenemia and left sensorineural hearing loss. Given that the patient and family members had no history of bleeding and thrombotic diseases, the patient had no oral and gum bleeding; no subcutaneous petechiae, ecchymosis, hematemesis, hemoptysis; no bleeding tendency such as melena, the patient was not given special treatment such as fibrinogen infusion, but only clinical observation. At end of follow-up, general condition of the patient was good. ⑤ The results of literature review showed that patients of abnormal fibrinogenemia with c. 104G>A (p.Arg35His) heterozygous mutation in exon 2 and c. 16A>G (p.Ile6Val) heterozygous mutation in exon 1 of FGA gene, which were the same mutations of the patient in this study, were 23 and 1 cases, respectively. Among them, only 2 patients with c. 104G>A (p.Arg35His) heterozygous mutation in exon 1 of FGA gene showed bleeding and thrombosis symptoms. Conclusions Abnormal fibrinogenemia has a variety of clinical manifestations. Some patients manifest as without any clinical symptoms, but others can also manifest as bleeding or thrombosis. The diagnosis of the disease is mainly based on its family history, clinical manifestations, abnormal results of blood coagulation tests, identification of genetic mutations, and adheres to the principle of individualization. No special treatment is required for asymptomatic abnormal fibrinogenemia patients without a history and family history of bleeding and thrombosis. Key words: Fibrinogens, abnormal; Mutation; Fibrinogen; Hemorrhage; Thrombosis; Abnormal fibrinogenemia