Hypofibrinogenemia and liver disease: a new case of Aguadilla fibrinogen and review of the literature

被引:23
作者
Casini, A. [1 ]
Sokollik, C. [2 ]
Lukowski, S. W. [3 ]
Lurz, E. [2 ]
Rieubland, C. [4 ]
de Moerloose, P. [1 ]
Neerman-Arbez, M. [1 ,3 ]
机构
[1] Univ Hosp Geneva, Angiol & Haemostasis, CH-1205 Geneva, Switzerland
[2] Fac Med Geneva, Geneva, Switzerland
[3] Univ Bern, Inselspital, Univ Childrens Hosp, Paediat Gastroenterol Hepatol & Nutr, CH-3010 Bern, Switzerland
[4] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland
关键词
congenital fibrinogen disorders; genetics; hypofibrinogenemia; liver disease; molecular models; mutation; ENDOPLASMIC-RETICULUM-STORAGE; GAMMA-CHAIN EXPRESSION; SIALIC-ACID; MUTATION; AUTOPHAGY; SUBSTITUTION; DYSFIBRINOGENEMIA; ACCUMULATION; DEGRADATION; CELLS;
D O I
10.1111/hae.12719
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
IntroductionFibrinogen storage disease (FSD) is characterized by hypofibrinogenemia and hepatic inclusions due to impaired release of mutant fibrinogen which accumulates and aggregates in the hepatocellular endoplasmic reticulum. Liver disease is variable. AimWe studied a new Swiss family with fibrinogen Aguadilla. In order to understand the molecular peculiarity of FSD mutations, fibrinogen Aguadilla and the three other causative mutations, all located in the D domain, were modelled. MethodThe proband is a Swiss girl aged 4 investigated because of fatigue and elevated liver enzymes. Protein structure models were prepared using the Swiss-PdbViewer and POV-Ray software. ResultsThe proband was found to be heterozygous for fibrinogen Aguadilla: FGG Arg375Trp. Familial screening revealed that her mother and maternal grandmother were also affected and, in addition, respectively heterozygous and homozygous for the hereditary haemochromatosis mutation HFE C282Y. Models of backbone and side-chain interactions for fibrinogen Aguadilla in a 10-angstrom region revealed the loss of five H-bonds and the gain of one H-bond between structurally important amino acids. The structure predicted for fibrinogen Angers showed a novel helical structure in place of hole a' on the outer edge of D likely to have a negative impact on fibrinogen assembly and secretion. ConclusionThe mechanism by which FSD mutations generate hepatic intracellular inclusions is still not clearly established although the promotion of aberrant intermolecular strand insertions is emerging as a likely cause. Reporting new cases is essential in the light of novel opportunities of treatment offered by increasing knowledge of the degradation pathway and autophagy.
引用
收藏
页码:820 / 827
页数:8
相关论文
共 33 条
[1]   Hepatic Fibrinogen Storage Disease Due to the Fibrinogen γ375 Arg → Trp Mutation "Fibrinogen Aguadilla" is present in Arabs [J].
Al-Hussaini, Abdulrahman ;
Altalhi, Abdulhadi ;
El Hag, Imad ;
AlHussaini, Hussa ;
Francalanci, Paola ;
Giovannoni, Isabella ;
Callea, Francesco .
SAUDI JOURNAL OF GASTROENTEROLOGY, 2014, 20 (04) :255-261
[2]   SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information [J].
Biasini, Marco ;
Bienert, Stefan ;
Waterhouse, Andrew ;
Arnold, Konstantin ;
Studer, Gabriel ;
Schmidt, Tobias ;
Kiefer, Florian ;
Cassarino, Tiziano Gallo ;
Bertoni, Martino ;
Bordoli, Lorenza ;
Schwede, Torsten .
NUCLEIC ACIDS RESEARCH, 2014, 42 (W1) :W252-W258
[3]   Fibrinogen brescia -: Hepatic endoplasmic reticulum storage and hypofibrinogenemia because of a γ284 Gly→Arg mutation [J].
Brennan, SO ;
Wyatt, J ;
Medicina, D ;
Callea, F ;
George, PM .
AMERICAN JOURNAL OF PATHOLOGY, 2000, 157 (01) :189-196
[4]   Novel fibrinogen γ375 Arg→Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia [J].
Brennan, SO ;
Maghzal, G ;
Shneider, BL ;
Gordon, R ;
Magid, MS ;
George, PM .
HEPATOLOGY, 2002, 36 (03) :652-658
[5]   Substitution (γ335Trp→Arg) in fibrinogen Fremantle causes diminished γ chain expression and increased sialic acid content [J].
Brennan, Stephen O. ;
Davis, Ryan L. .
THROMBOSIS AND HAEMOSTASIS, 2010, 104 (06) :1274-1276
[6]   Novel fibrinogen mutation γ314Thr→Pro (fibrinogen AI duPont) associated with hepatic fibrinogen storage disease and hypofibrinogenaemia [J].
Brennan, Stephen O. ;
Davis, Ryan L. ;
Conard, Katrina ;
Savo, Anthony ;
Furuya, Katryn N. .
LIVER INTERNATIONAL, 2010, 30 (10) :1541-1547
[7]   New fibrinogen substitution (γSer313Arg) causes diminished γ chain expression and hypodysfibrinogenaemia [J].
Brennan, Stephen O. ;
Davis, Ryan L. ;
Chitlur, Meera .
THROMBOSIS AND HAEMOSTASIS, 2010, 103 (02) :478-479
[8]  
CALLEA F, 1992, LIVER, V12, P357
[9]   γ-chain dysfibrinogenemias:: Molecular structure-function relationships of naturally occurring mutations in the γ chain of human fibrinogen [J].
Côté, HCF ;
Lord, ST ;
Pratt, KP .
BLOOD, 1998, 92 (07) :2195-2212
[10]   Congenital Fibrinogen Disorders: An Update [J].
de Moerloose, Philippe ;
Casini, Alessandro ;
Neerman-Arbez, Marguerite .
SEMINARS IN THROMBOSIS AND HEMOSTASIS, 2013, 39 (06) :585-595