{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T03:23:17Z","timestamp":1768706597311,"version":"3.49.0"},"reference-count":30,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2017,12,15]],"date-time":"2017-12-15T00:00:00Z","timestamp":1513296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen \u03b3. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB\u2013lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the \u201cend-to-end\u201d interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon.<\/jats:p>","DOI":"10.3390\/ijms18122717","type":"journal-article","created":{"date-parts":[[2017,12,15]],"date-time":"2017-12-15T12:23:56Z","timestamp":1513340636000},"page":"2717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage"],"prefix":"10.3390","volume":"18","author":[{"given":"Francesco","family":"Callea","sequence":"first","affiliation":[{"name":"Department Pathology and Molecular Histopathology, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9980-6594","authenticated-orcid":false,"given":"Isabella","family":"Giovannoni","sequence":"additional","affiliation":[{"name":"Department Pathology and Molecular Histopathology, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sinan","family":"Sari","sequence":"additional","affiliation":[{"name":"Department Pediatric Gastroenterology, Gazi University Ankara, 06560 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esendagli","family":"Guldal","sequence":"additional","affiliation":[{"name":"Department Pathology, Gazi University Ankara, 06560 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Buket","family":"Dalgic","sequence":"additional","affiliation":[{"name":"Department Pediatric Gastroenterology, Gazi University Ankara, 06560 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gulen","family":"Akyol","sequence":"additional","affiliation":[{"name":"Department Pathology, Gazi University Ankara, 06560 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyoshi","family":"Sogo","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Tobu Hospital 3-6-1, Shimosueyoshi, Tsurumi Ward, Yokohama City, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulrahman","family":"Al-Hussaini","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, College of Medicine, Alfaisal University Riyadh 11525, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Maggiore","sequence":"additional","affiliation":[{"name":"Section of Pediatrics, Department of Medical Sciences, University of Ferrara, University Hospital Arcispedale Sant\u2019Anna, 44100 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Bartuli","sequence":"additional","affiliation":[{"name":"Rare Disease and Medical Genetics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renata","family":"Boldrini","sequence":"additional","affiliation":[{"name":"Department Pathology and Molecular Histopathology, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Francalanci","sequence":"additional","affiliation":[{"name":"Department Pathology and Molecular Histopathology, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2757-849X","authenticated-orcid":false,"given":"Emanuele","family":"Bellacchio","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases, Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,12,15]]},"reference":[{"key":"ref_1","unstructured":"Callea, F., De Vos, R., and Pinackat, J. (1987). Hereditary Hypofibrinogenemia with Hepatic Storage of Fibrinogen: A New Endoplasmic Reticulum Storage Disease, in Fibrinogen 2, Elsevier."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/j.1600-0676.1992.tb00589.x","article-title":"Hepatic endoplasmic reticulum storage diseases","volume":"12","author":"Callea","year":"1992","journal-title":"Liver"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0002-9440(10)64530-0","article-title":"Fibrinogen brescia: Hepatic endoplasmic reticulum storage and hypofibrinogenemia because of a gamma284 Gly\u2192Arg mutation","volume":"157","author":"Brennan","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_4","unstructured":"Callea, F., Tortora, O., and Kojima, T. (1988). Hypofibrinogenemia and Fibrinogen Storage Disease, in Fibrinogen 3, Elsevier."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1053\/jhep.2002.35063","article-title":"Novel fibrinogen gamma375 Arg\u2192Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia","volume":"36","author":"Brennan","year":"2002","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1111\/j.1538-7836.2007.02713.x","article-title":"Fibrinogen angers with a new deletion (gamma GVYYQ 346\u2013350) causes hypofibrinogenemia with hepatic storage","volume":"5","author":"Dib","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1111\/j.1478-3231.2010.02312.x","article-title":"Novel fibrinogen mutation gamma314Thr\u2192Pro (fibrinogen AI duPont) associated with hepatic fibrinogen storage disease and hypofibrinogenaemia","volume":"30","author":"Brennan","year":"2010","journal-title":"Liver Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1111\/jth.13021","article-title":"Hepatic fibrinogen storage disease: Identification of two novel mutations (p.Asp316Asn, fibrinogen Pisa and p.Gly366Ser, fibrinogen Beograd) impacting on the fibrinogen gamma-module","volume":"13","author":"Asselta","year":"2015","journal-title":"J. Thromb. Haemost."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.pathol.2017.03.007","article-title":"A novel fibrinogen gamma chain mutation (c.1096C>G; p.His340Asp), fibrinogen Ankara, causing hypofibrinogenaemia and hepatic storage","volume":"49","author":"Callea","year":"2017","journal-title":"Pathology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1111\/liv.12914","article-title":"Fibrinogen storage disease and cirrhosis associated with hypobetalipoproteinemia owing to fibrinogen Aguadilla in a Turkish child","volume":"35","author":"Sari","year":"2015","journal-title":"Liver Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1097\/MPG.0b013e31817ed7ea","article-title":"Fibrinogen storage disease caused by Aguadilla mutation presenting with hypobeta-lipoproteinemia and considerable liver disease","volume":"49","author":"Sogo","year":"2009","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_12","first-page":"179","article-title":"Pseudo ground-glass hepatocytes immunoreactive for fibrinogen","volume":"7","author":"Callea","year":"1985","journal-title":"Occurrence and significance in liver biopsies. Istiocitopatologia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1529\/biophysj.104.046235","article-title":"Assembly of lipoprotein particles containing apolipoprotein-B: Structural model for the nascent lipoprotein particle","volume":"88","author":"Richardson","year":"2005","journal-title":"Biophys. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.jpeds.2005.10.007","article-title":"Severe liver disease in early childhood due to fibrinogen storage and de novo gamma375Arg\u2192Trp gene mutation","volume":"148","author":"Francalanci","year":"2006","journal-title":"J. Pediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1097\/01.pas.0000209848.59670.2c","article-title":"Fibrinogen gamma375 arg\u2192trp mutation (fibrinogen aguadilla) causes hereditary hypofibrinogenemia, hepatic endoplasmic reticulum storage disease and cirrhosis","volume":"30","author":"Rougemont","year":"2006","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.jhep.2013.05.018","article-title":"Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease","volume":"59","author":"Puls","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"255","DOI":"10.4103\/1319-3767.136985","article-title":"Hepatic fibrinogen storage disease due to the fibrinogen gamma375 Arg\u2192Trp mutation \u201cfibrinogen Aguadilla\u201d is present in Arabs","volume":"20","author":"Altalhi","year":"2014","journal-title":"Saudi J. Gastroenterol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1111\/hae.12719","article-title":"Hypofibrinogenemia and liver disease: A new case of Aguadilla fibrinogen and review of the literature","volume":"21","author":"Casini","year":"2015","journal-title":"Haemophilia"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhang, M.H., Knisely, A.S., Wang, N.L., Gong, J.Y., and Wang, J.S. (2016). Fibrinogen storage disease in a Chinese boy with de novo fibrinogen Aguadilla mutation: Incomplete response to carbamazepine and ursodeoxycholic acid. BMC Gastroenterol., 16.","DOI":"10.1186\/s12876-016-0507-3"},{"key":"ref_20","unstructured":"Kane, J.P., and Havel, R.J. (2000). Disorders of the Biogenesis and Secretion of Lipoproteins Containing the B Apolipoproteins, McGraw-Hill Professional."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24270","DOI":"10.1074\/jbc.M702442200","article-title":"Missense mutations in APOB within the betaalpha1 domain of human APOB-100 result in impaired secretion of ApoB and ApoB-containing lipoproteins in familial hypobetalipoproteinemia","volume":"282","author":"Burnett","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/38947","article-title":"Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin","volume":"389","author":"Spraggon","year":"1997","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9398","DOI":"10.1021\/bi025674w","article-title":"Lipid-protein interactions in lipovitellin","volume":"41","author":"Thompson","year":"2002","journal-title":"Biochemistry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1097\/MOL.0b013e32835aebe7","article-title":"Microsome-associated lumenal lipid droplets in the regulation of lipoprotein secretion","volume":"24","author":"Yao","year":"2013","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/j.1749-6632.2001.tb03538.x","article-title":"Genetic and immunological characterization of fibrinogen inclusion bodies in patients with hepatic fibrinogen storage and liver disease","volume":"936","author":"Medicina","year":"2001","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1111\/j.1749-6632.2001.tb03535.x","article-title":"Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion","volume":"936","author":"Redman","year":"2001","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.2353\/ajpath.2006.051097","article-title":"Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: An explanation for liver disease","volume":"168","author":"Kruse","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"456S","DOI":"10.1093\/jn\/129.2.456S","article-title":"Apolipoprotein B in the rough endoplasmic reticulum: Translation, translocation and the initiation of lipoprotein assembly","volume":"129","author":"Shelness","year":"1999","journal-title":"J. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"178","DOI":"10.7555\/JBR.28.20140019","article-title":"Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion","volume":"28","author":"Fisher","year":"2014","journal-title":"J. Biomed. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1097\/MPG.0b013e318232c477","article-title":"Long-term outcome of liver disease-related fibrinogen aguadilla storage disease in a child","volume":"53","author":"Maggiore","year":"2011","journal-title":"J. Pediatr. Gastroenterol. Nutr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/12\/2717\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:54:08Z","timestamp":1760208848000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/12\/2717"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,15]]},"references-count":30,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["ijms18122717"],"URL":"https:\/\/doi.org\/10.3390\/ijms18122717","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,15]]}}}