The fibrous form of intracellular inclusion bodies in recombinant variant fibrinogen-producing cells is specific to the hepatic fibrinogen storage disease-inducible variant fibrinogen

Arai, Shinpei; Ogiwara, Naoko; Mukai, Saki; Takezawa, Yuka; Sugano, Mitsutoshi; Honda, Takayuki; Okumura, Nobuo

doi:10.1007/s12185-017-2185-5

Cited by 4 publications

(6 citation statements)

References 29 publications

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“…Out of those, eight mutations (one missense mutation in Aα chain, six missense mutations in γ chain, and one in-frame deletion of five amino acids in γ chain) are found to cause HFSD in an autosomal dominant manner [ 164 , 174 , 175 , 237 , 238 , 239 , 240 ]. Interestingly, unlike other missense mutations found in congenital fibrinogen disorders, HFSD mutants form intracellular inclusions in the ER [ 163 , 241 ].…”

Section: Er Storage Diseasesmentioning

confidence: 99%

Protein Aggregation in the ER: Calm behind the Storm

Sun

2021

Cells

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As one of the largest organelles in eukaryotic cells, the endoplasmic reticulum (ER) plays a vital role in the synthesis, folding, and assembly of secretory and membrane proteins. To maintain its homeostasis, the ER is equipped with an elaborate network of protein folding chaperones and multiple quality control pathways whose cooperative actions safeguard the fidelity of protein biogenesis. However, due to genetic abnormalities, the error-prone nature of protein folding and assembly, and/or defects or limited capacities of the protein quality control systems, nascent proteins may become misfolded and fail to exit the ER. If not cleared efficiently, the progressive accumulation of misfolded proteins within the ER may result in the formation of toxic protein aggregates, leading to the so-called “ER storage diseases”. In this review, we first summarize our current understanding of the protein folding and quality control networks in the ER, including chaperones, unfolded protein response (UPR), ER-associated protein degradation (ERAD), and ER-selective autophagy (ER-phagy). We then survey recent research progress on a few ER storage diseases, with a focus on the role of ER quality control in the disease etiology, followed by a discussion on outstanding questions and emerging concepts in the field.

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Section: Er Storage Diseasesmentioning

confidence: 99%

Protein Aggregation in the ER: Calm behind the Storm

Sun

2021

Cells

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“…During coagulation, thrombin cleaves fibrinogen, releasing fibrinopeptide A and fibrinopeptide B from the Nterminus of the Aα chain (residues of Aα. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and Bβchain (residues of Bβ. [1][2][3][4][5][6][7][8][9][10][11][12][13][14], respectively, and converting fibrinogen to fibrin monomers [26,27].…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and Bβchain (residues of Bβ. [1][2][3][4][5][6][7][8][9][10][11][12][13][14], respectively, and converting fibrinogen to fibrin monomers [26,27]. Thus, the AαR16 residue is crucial for thrombin cleavage for fibrin monomer formation.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with CFDs are at higher risk of bleeding or thrombotic complication than healthy individuals, and in some cases infertility has also been reported [8,9]. Furthermore, several Hypo variants on the C-terminal side of the γ chain lead to intrahepatic accumulation of fibrinogen, resulting in life-threatening liver disease (fibrinogen storage disease) [10][11][12]. Most asymptomatic patients are identified by coagulation screening tests, and it is important to determine whether lower fibrinogen levels are due to the congenital or acquired background.…”

Section: Introductionmentioning

confidence: 99%

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Automated screening procedure for the phenotypes of congenital fibrinogen disorders using novel parameters, |min1|c and Ac/|min1|c, obtained from clot waveform analysis using the Clauss method

Arai

Kamijo

Kaido

et al. 2021

Clinica Chimica Acta

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“…Wild-type fibrinogen-synthesizing (γp.352C-CHO) cells were stained in a perinuclear network pattern (abbreviated as 'N'). Variant fibrinogen-synthesizing cell lines, γp.R401W showed two characteristic patterns, namely, scattered large-granular bodies (abbreviated as 'LG'), fibrous forms of two subpolar sites of the nucleus (abbreviated as 'F'), previously reported as a specific feature in fibrinogen variants causing hepatic ER storage disease [23]. Although C352S-CHO cells showed 'N' and 'LG' staining patterns and the frequency of 'LG' was 23.00 %, the other three variant fibrinogen-synthesizing cell lines (γp.C352Y, R and F) were stained with only the 'N' pattern.…”

Section: Fluorescent Fibrinogen Stainingmentioning

confidence: 98%

Novel variant fibrinogen γp.C352R produced hypodysfibrinogenemia leading to a bleeding episode and failure of infertility treatment

et al. 2021

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Introduction:We identified a patient with a novel heterozygous variant fibrinogen, γp.C352R (Niigata II; N-II), who had a bleeding episode and failed infertility treatment and was suspected to have hypodysfibrinogenemia based on low and discordant fibrinogen levels (functional assay: 0.33 g/L, immunological assay: 0.91 g/L). We analyzed the mechanism of this rare phenotype of a congenital fibrinogen disorder. Materials and methods:Patient plasma fibrinogen was purified and protein characterization and thrombin-catalyzed fibrin polymerization performed. Recombinant fibrinogen-producing Chinese hamster ovary (CHO) cells were established and the assembly and secretion of variant fibrinogen analyzed by ELISA and western blotting.Results: Purified N-II plasma fibrinogen had a small lower molecular weight band below the normal γ-chain and slightly reduced fibrin polymerization. A limited proportion of p.C352R fibrinogen was secreted into the culture medium of established CHO cell lines, but the γ-chain of p.C352R was synthesized and variant fibrinogen was assembled inside the cells. Conclusion:We demonstrated that fibrinogen N-II, γp.C352R, was associated with markedly reduced secretion of variant fibrinogen from CHO cells, that fibrin polymerization of purified plasma fibrinogen was only slightly affected, and that fibrinogen N-II produces hypodysfibrinogenemia in plasma.

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The fibrous form of intracellular inclusion bodies in recombinant variant fibrinogen-producing cells is specific to the hepatic fibrinogen storage disease-inducible variant fibrinogen

Cited by 4 publications

References 29 publications

Protein Aggregation in the ER: Calm behind the Storm

Protein Aggregation in the ER: Calm behind the Storm

Automated screening procedure for the phenotypes of congenital fibrinogen disorders using novel parameters, |min1|c and Ac/|min1|c, obtained from clot waveform analysis using the Clauss method

Novel variant fibrinogen γp.C352R produced hypodysfibrinogenemia leading to a bleeding episode and failure of infertility treatment

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