Carola Dröge1, Michele Bonus2, Ulrich Baumann3, Caroline Klindt1, Elke Lainka4, Simone Kathemann4, Florian Brinkert5, Enke Grabhorn5, Eva-Doreen Pfister3, Daniel Wenning6, Alexander Fichtner6, Daniel N Gotthardt7, Karl Heinz Weiss7, Patrick McKiernan8, Ratna Dua Puri9, I C Verma9, Stefanie Kluge1, Holger Gohlke2, Lutz Schmitt10, Ralf Kubitz1, Dieter Häussinger11, Verena Keitel12. 1. Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany. 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Germany. 3. Pediatric Gastroenterology and Hepatology, Department for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Germany. 4. Department for Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, Clinic for Pediatrics II, University Children's Hospital Essen, University Duisburg-Essen, Germany. 5. Pediatric Gastroenterology and Hepatology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Germany. 6. Department of General Pediatrics, Heidelberg University Hospital, Germany. 7. Department of Internal Medicine IV, University Hospital Heidelberg, Germany. 8. Pittsburgh Liver Research Center, University of Pittsburgh and Children's Hospital of Pittsburgh of UPMC, Pittsburgh, USA. 9. Institute of Medical Genetics & Genomics, Sir Ganga Ram Hospital, New Delhi, India. 10. Institute of Biochemistry, Heinrich Heine University Düsseldorf, Germany. 11. Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany. Electronic address: haeussin@uni-duesseldorf.de. 12. Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany. Electronic address: verena.keitel@med.uni-duesseldorf.de.
Abstract
BACKGROUND & AIMS: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling. RESULTS: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect. CONCLUSIONS: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. LAY SUMMARY: FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.
BACKGROUND & AIMS: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestaticpatients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling. RESULTS: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect. CONCLUSIONS: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. LAY SUMMARY:FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.
Authors: Giovanni Vitale; Stefano Gitto; Francesco Raimondi; Alessandro Mattiaccio; Vilma Mantovani; Ranka Vukotic; Antonietta D'Errico; Marco Seri; Robert B Russell; Pietro Andreone Journal: J Gastroenterol Date: 2017-12-13 Impact factor: 7.527
Authors: Paula M Hertel; Laura N Bull; Richard J Thompson; Nathan P Goodrich; Wen Ye; John C Magee; Robert H Squires; Lee M Bass; James E Heubi; Grace E Kim; Sarangarajan Ranganathan; Kathleen B Schwarz; Molly A Bozic; Simon P Horslen; Matthew S Clifton; Yumirle P Turmelle; Frederick J Suchy; Riccardo A Superina; Kasper S Wang; Kathleen M Loomes; Binita M Kamath; Ronald J Sokol; Benjamin L Shneider Journal: J Pediatr Gastroenterol Nutr Date: 2021-08-01 Impact factor: 3.288
Authors: Stephanie Barbara Schatz; Christoph Jüngst; Verena Keitel-Anselmo; Ralf Kubitz; Christina Becker; Patrick Gerner; Eva-Doreen Pfister; Imeke Goldschmidt; Norman Junge; Daniel Wenning; Stephan Gehring; Stefan Arens; Dirk Bretschneider; Dirk Grothues; Guido Engelmann; Frank Lammert; Ulrich Baumann Journal: Hepatol Commun Date: 2018-03-22