scholarly journals A missense mutation in ABCB4 gene involved in progressive familial intrahepatic cholestasis type 3 leads to a folding defect that can be rescued by low temperature

Hepatology ◽  
2008 ◽  
Vol 49 (4) ◽  
pp. 1218-1227 ◽  
Author(s):  
Jean-Louis Delaunay ◽  
Anne-Marie Durand-Schneider ◽  
Danièle Delautier ◽  
Alegna Rada ◽  
Julien Gautherot ◽  
...  
Keyword(s):  
Low Temperature ◽  
Missense Mutation ◽  
Intrahepatic Cholestasis ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Folding Defect ◽  
Abcb4 Gene ◽  
Type 3

scholarly journals A Novel Compound Heterozygous Mutation in ABCB4 Gene Leading to Cholelithiasis, Progressive Familial Intrahepatic Cholestasis (Type 3), and Cirrhosis in a Child

2020 ◽  
Vol 10 (01) ◽  
pp. e134-e136
Author(s):  
Nida Mirza ◽  
Smita Malhotra ◽  
Anupam Sibal
Keyword(s):  
Intrahepatic Cholestasis ◽  
Gall Stone ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Initial Symptom ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Presenting Symptoms ◽  
Abcb4 Gene ◽  
Type 3

AbstractProgressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive disorders of childhood which presents with intermittent or progressive episodes of cholestasis, with jaundice and pruritus as most common presenting symptoms. PFIC type 3 occurs due to mutations in the ABCB4 gene, mutation in this gene has wide spectrum of features which include intrahepatic stones, cholelithiasis, PFIC type 3, and intrahepatic cholestasis of pregnancy. Here, we are reporting a peculiar case of young male adolescent with novel variant compound heterozygote missense mutation in ABCB4 gene who had gall stone as initial symptom, followed by symptoms of PFIC and eventually decompensated chronic liver disease.

scholarly journals Evaluation of a Novel Missense Mutation in ABCB4 Gene Causing Progressive Familial Intrahepatic Cholestasis Type 3

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Komal Saleem ◽  
Qingbo Cui ◽  
Tahir Zaib ◽  
Siqi Zhu ◽  
Qian Qin ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Genetic Screening ◽  
Intrahepatic Cholestasis ◽  
Functional Characterization ◽  
Mutant Protein ◽  
Wild Type ◽  
Lysosomal Degradation ◽  
Hepatic Disorder ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Type 3

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a hepatic disorder occurring predominantly in childhood and is difficult to diagnose. PFIC3, being a rare autosomal recessive disease, is caused by genetic mutations in both alleles of ABCB4, resulting in the disruption of the bile secretory pathway. The identification of pathogenic effects resulting from different mutations in ABCB4 is the key to revealing the internal cause of disease. These mutations cause truncation, instability, misfolding, and impaired trafficking of the MDR3 protein. Here, we reported a girl, with a history of intrahepatic cholestasis and progressive liver cirrhosis, with an elevated gamma-glutamyltransferase level. Genetic screening via whole exome sequencing found a novel homozygous missense mutation ABCB4:c.1195G>C:p.V399L, and the patient was diagnosed with PFIC3. Various computational tools predicted the variant to be deleterious and evolutionary conserved. For functional characterization studies, plasmids, encoding ABCB4 wild-type and selected established mutant constructs, were expressed in human embryonic kidney (HEK-293T) and hepatocellular carcinoma (HepG2) cells. In vitro expression analysis observed a reduced expression of mutant protein compared to wild-type protein. We found that ABCB4 wild type was localized at the apical canalicular membrane, while mutant p.V399L showed intracellular retention. Intracellular mistrafficking proteins usually undergo proteasomal or lysosomal degradation. We found that after treatment with proteasomal inhibitor MG132 and lysosomal inhibitor bafilomycin A1, MDR3 expression of V399L was significantly increased. A decrease in MDR3 expression of mutant V399L protein may be a result of proteasomal or lysosomal degradation. Pharmacological modulator cyclosporin A and intracellular low temperature (30°C) treatment significantly rescued both the folding defect and the active maturation of the mutant protein. Our study identified a novel pathogenic mutation which expanded the mutational spectrum of the ABCB4 gene and may contribute to understanding the molecular basis of PFIC3. Therefore, genetic screening plays a conclusive role in the diagnosis of rare heterogenic disorders like PFIC3.

scholarly journals Approach and management considerations in low phospholipid associated cholelithiasis (LPAC) syndrome

2018 ◽  
Vol 6 (11) ◽  
pp. 3794
Author(s):  
Indrajit Suresh ◽  
Lokesh E. ◽  
Amrit Nanaiah ◽  
Soumya Ganesh Nanaiah ◽  
Suhas C. ◽  
...  
Keyword(s):  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Intrahepatic Cholestasis ◽  
Biliary Obstruction ◽  
Young Patients ◽  
Close Monitoring ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Intrahepatic Calculi ◽  
Abcb4 Gene ◽  
Type 3

Low phospholipid associated cholelithiasis (LPAC) syndrome, first described in 2001, could be the causality in a significant number of young patients with cholelithiasis, who have a recurrence of symptoms despite cholecystectomy. A mutation of the ABCB4/MDR3 gene, causes a disruption in the translocation of phosphatidylcholine, resulting in bile acid mediated biliary tract injury. The ABCB4 gene is also implicated in other diseases such as progressive familial intrahepatic cholestasis type 3, which is greater in severity and tools like genotyping can aid the physician in prognostication, as well as determining the response to medical therapy. A few symptomatic patients develop features of biliary obstruction due to intrahepatic calculi, and they require interventions-which may be endoscopic or surgical in nature. Although a majority of patients with LPAC syndrome respond well to ursodeoxycholic acid (UDCA) therapy, close monitoring is warranted to keep a check on disease progression.

A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis

2020 ◽  
Vol 33 (5) ◽  
pp. 665-669
Author(s):  
Aynur Küçükçongar Yavaş ◽  
Büşra Çavdarlı ◽  
Özlem Ünal Uzun ◽  
Ayşen Uncuoğlu ◽  
Mehmet Gündüz
Keyword(s):  
Primary Biliary Cirrhosis ◽  
Intrahepatic Cholestasis ◽  
Density Lipoprotein ◽  
Etiologic Factor ◽  
Compound Heterozygous ◽  
Cholestatic Liver Disease ◽  
Biliary Cirrhosis ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Turkish Patient ◽  
Type 3

AbstractBackgroundProgressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C.Case presentationHere we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol.ConclusionThis is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.

Nutritional assessment in patients with progressive familial intrahepatic cholestasis type 3

2021 ◽  
Vol 46 ◽  
pp. S767
Author(s):  
M. Baycheva ◽  
R. Shentova-Eneva ◽  
D. Kofinova ◽  
P. Hadzhiyski ◽  
H. Naydenov ◽  
...  
Keyword(s):  
Intrahepatic Cholestasis ◽  
Nutritional Assessment ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Type 3

Functional analysis ofABCB4mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity

Gut ◽  
2014 ◽  
Vol 64 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Raquel Gordo-Gilart ◽  
Sara Andueza ◽  
Loreto Hierro ◽  
Pilar Martínez-Fernández ◽  
Daniel D'Agostino ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Clinical Outcomes ◽  
Intrahepatic Cholestasis ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Type 3
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