Hereditary Hypofibrinogenemia with Hepatic Storage

Asselta, Rosanna; Paraboschi, Elvezia Maria; Duga, Stefano

doi:10.3390/ijms21217830

Cited by 16 publications

(28 citation statements)

References 62 publications

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“…Obstacles in fibrinogen secretion result in the accumulation of mutated peptide chains in hepatocytes strongly predisposes the development of varying degrees of severe chronic liver disease (27). In the present study, clinically, normal liver function in patients indicates that although fibrinogen secretion is impaired, mutant peptide chains are less likely to accumulate in liver cells.…”

Section: Discussionsupporting

confidence: 47%

A novel fibrinogen γ-chain frameshift mutation, p. Cys365Phefs*41, causing hypofibrinogenemia with bleeding phenotype in a Chinese family

et al. 2021

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Background: Congenital hypofibrinogenemia is a rare bleeding disease that is classified as the quantitative deficient type. In the present study, investigated the relationship between the genotype and phenotype in a family with hypofibrinogenemia. Methods:The proband was aware of a predisposition to bleeding. Functional analysis was performed for her all family members, including coagulation function tests, thrombus molecular markers, thromboelastography, scanning electron microscopy, DNA sequencing, and high-performance liquid chromatography-mass spectrometry (HPLC-MS). Pathogenicity analysis and protein modeling of mutant amino acids were also performed.Results: A novel heterozygous mutation in c.1094delG was detected in FGG exon 8, which resulted in p.Cys365Phefs*41 (containing the signal peptide) in the proband and her mother, who showed a corresponding decrease in fibrinogen function and levels. Thromboelastography indicated that the strength of their blood clots decreased and they had an increased risk of bleeding. The proband fibrin network structure was looser than healthy controls, with large pores in the network, which increased the permeability of lytic enzymes.Results of HPLC-MS showed a lack of mutant peptide chain expression in their plasma, indicating that the family had congenital hypofibrinogenemia, with a clinical phenotype that is related to the degree of fibrinogen deficiency. The mutation truncated the γ-peptide chain and destroyed the functional structure of fibrinogen, including the γ352Cys-γ365Cys disulfide bond. The truncated peptide chains may also lead to nonsense-mediated decay. Conclusions:The mutation induced a structural change at the carboxyl-terminal of the fibrinogen molecule, leading to fibrinogen secretion dysfunction.

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Section: Discussionsupporting

confidence: 47%

A novel fibrinogen γ-chain frameshift mutation, p. Cys365Phefs*41, causing hypofibrinogenemia with bleeding phenotype in a Chinese family

et al. 2021

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“…ZAAT misfolds and aggregates in the ER of hepatocytes, leading to ER stress, which increases the incidence of liver damage, fibrosis, cirrhosis, and carcinogenesis [130][131][132][133]. Mutant fibrinogen also accumulates within the hepatocellular ER, leading to inherited hypofibrinogenemia [134].…”

Section: Alpha-1 Antitrypsin Deficiency (Aatd)mentioning

confidence: 99%

“…XBP1s interacts with the WW domain of PIN1 via the Ser288-Pro motif of XBP1s. (B) The p38 MAPK directly phosphorylates the Thr48 and Ser61 residues of XBP1s, thereby enhancing the nuclear translocation of XBP1s[134]. (C) Insulin induces the interaction of XBP1s with p85α and p85β, the regulatory subunits of PI3K, leading to increased nuclear translocation of XBP1s.…”

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confidence: 99%

Roles of XBP1s in Transcriptional Regulation of Target Genes

2021

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The spliced form of X-box binding protein 1 (XBP1s) is an active transcription factor that plays a vital role in the unfolded protein response (UPR). Under endoplasmic reticulum (ER) stress, unspliced Xbp1 mRNA is cleaved by the activated stress sensor IRE1α and converted to the mature form encoding spliced XBP1 (XBP1s). Translated XBP1s migrates to the nucleus and regulates the transcriptional programs of UPR target genes encoding ER molecular chaperones, folding enzymes, and ER-associated protein degradation (ERAD) components to decrease ER stress. Moreover, studies have shown that XBP1s regulates the transcription of diverse genes that are involved in lipid and glucose metabolism and immune responses. Therefore, XBP1s has been considered an important therapeutic target in studying various diseases, including cancer, diabetes, and autoimmune and inflammatory diseases. XBP1s is involved in several unique mechanisms to regulate the transcription of different target genes by interacting with other proteins to modulate their activity. Although recent studies discovered numerous target genes of XBP1s via genome-wide analyses, how XBP1s regulates their transcription remains unclear. This review discusses the roles of XBP1s in target genes transcriptional regulation. More in-depth knowledge of XBP1s target genes and transcriptional regulatory mechanisms in the future will help develop new therapeutic targets for each disease.

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“…Clinical signs of afibrinogenemia and hypofibrinogenemia are various, ranging from being asymptomatic to experiencing dangerous life-threatening bleeding or thromboembolic episodes [1,[10][11][12]. In addition, we also know a type of hypofibrinogenemia that is associated with comorbid liver disease, known as hepatic fibrinogen storage disease [13].…”

Section: Classification and Terminology Of Congenital Fibrinogen Disordersmentioning

confidence: 99%

Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management

et al. 2021

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Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.

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Hereditary Hypofibrinogenemia with Hepatic Storage

Cited by 16 publications

References 62 publications

A novel fibrinogen γ-chain frameshift mutation, p. Cys365Phefs*41, causing hypofibrinogenemia with bleeding phenotype in a Chinese family

A novel fibrinogen γ-chain frameshift mutation, p. Cys365Phefs*41, causing hypofibrinogenemia with bleeding phenotype in a Chinese family

Roles of XBP1s in Transcriptional Regulation of Target Genes

Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management

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