Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

Abstract

Alpha-1-antitrypsin (AAT) and fibrinogen are secretory acute phase reactant proteins. Circulating AAT and fibrinogen are synthesized exclusively in the liver. Mutations in the encoding genes result in conformational abnormalities of the two molecules that aggregate within the rough endoplasmic reticulum (RER) instead of being regularly exported. That results in AAT-deficiency (AATD) and in hereditary hypofibrinogenemia with hepatic storage (HHHS). The association of plasma deficiency and liver storage identifies a new group of pathologies: endoplasmic reticulum storage disease (ERSD).

A novel FGG missense variant associated with fibrinogen storage disease in a large family from Quebec

“…An intriguing part of our results is the variability of the liver involvement, with older individuals apparently unaffected both from a clinical and a laboratory standpoint. While some authors have described liver involvement to be an ubiquitous hallmark of this condition, 4 others have reported variability and even absence of liver involvement amongst carriers of the same mutation, even if the same family, as observed in our cohort. 3 It has been hypothesized that this variability could stem from the presence of concomitant genetic defects in modifier genes.…”

“…2 Hypofibrinogenemia with fibrinogen storage disease (FSD) is a sub-type of hypofibrinogenemia, also known as type 2D, characterized by the accumulation and aggregation of mutant fibrinogen in hepatocytes. 3,4 First described in 1981, 5 the phenotype of FSD is characterized by bleeding diathesis, often proportionate to fibrinogen levels and revealed by mucocutaneous or post-procedural bleeding, as well as thrombosis and variable liver injury, ranging from the absence of symptoms up to end-stage liver disease and cirrhosis.…”

“…1 FSDs are believed to arise when variant of the Cterminal domain of γ chains impacts protein formation in hepatocytes, leading to spontaneous aggregation of fibrinogen polymers in the rough endoplasmic reticulum (RER), in turn causing cell engorgement and over-distension of RER cisternae interfering with other organelles and cell functions. 4 To date, eight disease-associated variants in FGG, on chromosome 4q31.3, have been reported as responsible for this rare autosomal dominant condition, all located in exons 8 or 9 of the FGG gene, with the Aguadilla variant appearing to be the most common. 6,7 Here, we present an unreported FGG disease-associated variant first detected in a 3-year-old male during the investigation of hepatic transaminitis following adenovirus infection, with abnormal prothrombin time, which triggered more extensive coagulation testing.…”

“…Marie-Claude Pelland-Marcotte 1,2 Adelina-Teona Avram 3 Hélène Néron 3 Christine Demers 3 Julie Castilloux 4 Julie Gauthier 5 Marguerite Neerman-Arbez 7,8 Alessandro Casini 6,8 Georges-Etienne Rivard 9 1 Department of Paediatrics, Division of Haematology, Centre Mère Enfant Soleil, Centre Hospitalier de l'Université de Québec, Quebec City, Canada 2 Centre de recherche du CHU de Québec, axe Reproduction, santé de la…”

Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside

“…This selective degradation of pathological protein aggregates suggests the therapeutic potential of increasing ER protein clearance activity in the ERSDs. Since some ERSDs have been discussed elsewhere ( Kuscuoglu et al, 2018 ; Callea et al, 2021 ; Li and Sun, 2021 ), here we pay more attention on two representative forms of ERADs.…”