Year 2019 / Volume 111 / Number 10
Original
Clinical characteristics and genetic profiles of young and adult patients with cholestatic liver disease

775-788

DOI: 10.17235/reed.2019.6168/2019

Minh Tuan Huynh, Truong-Tam Nguyen, Sophie Grison, Olivier Lascols, Eric Fernandez, Véronique Barbu,

Abstract
Background and aims: heterozygous ABCB4, ABCB11 and ATP8B1 sequence variants were previously reported to be associated with low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis and biliary lithiasis. The present study aimed to identify the presence of sequence variations in genes responsible for Mendelian liver disorders in patients with cholestatic liver disease. Methods: targeted massive parallel sequencing of a panel of genes involved in bile acid homeostasis was performed in 105 young and adult patients with cholestatic liver disease in our laboratory for molecular diagnosis. The effects of novel variants were evaluated using bioinformatics prediction tools and the Protter and Phyre2 software programs were used to create 2D, 3D topology protein modeling. Genotype-phenotype correlation was established according to molecular analysis and clinical records. Results: twenty novel heterozygous ABCB4 sequence variations, one heterozygous ABCB4 large intragenic deletion and only one novel missense variant in ABCB11 and ATP8B1 were identified. Interestingly, heterozygous and homozygous SLC4A2 missense variants were detected in patients with low phospholipid-associated cholelithiasis. Two patients harbored heterozygous GPBAR1 variants. Common variants such as homozygous ABCB11 p.Val444Ala and heterozygous ABCG8 p.Asp19His were also identified in 12 cases. Conclusions: forty-eight variants were identified in five genes including ABCB4, ABCB11, ATP8B1, SLC4A2 and GPBAR1, twenty-five of which were novel. This study expands the phenotypic and mutational spectrum in genes involved in bile acid homeostasis and highlights the genetic and phenotypic heterogeneity in patients with inherited liver disorders.
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References
1. Klomp LW, Vargas JC, van Mil SW, Pawlikowska L, Strautnieks SS, van Eijk MJ, Juijn JA et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004; 40: 27-38.
2. Dixon PH, Sambrotta M, Chambers J, Taylor-Harris P, Syngelaki A, Nicolaides K, Knisely AS et al. An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep 2017; 7: 11823.
3. Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, Bernard O, Jacquemin E. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology 2010; 51: 1645-1655.
4. van Mil SW, van der Woerd WL, van der Brugge G, Sturm E, Jansen PL, Bull LN, van den Berg IE et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 2004; 127: 379-384.
5. van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF, Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Pract Res Clin Gastroenterol 2010; 24: 541-553.
6. Bull LN, Thompson RJ. Progressive Familial Intrahepatic Cholestasis. Clin Liver Dis 2018; 22: 657-669.
7. Hov JR, Keitel V, Laerdahl JK, Spomer L, Ellinghaus E, ElSharawy A, Melum E et al. Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis. PLoS One 2010; 5: e12403. doi: 10.1371/journal.pone.0012403.
8. Medina JF. Role of the anion exchanger 2 in the pathogenesis and treatment of primary biliary cirrhosis. Dig Dis 2011; 29: 103-112.
9. Donepudi AC, Boehme S, Li F, Chiang JY. G-protein-coupled bile acid receptor plays a key role in bile acid metabolism and fasting-induced hepatic steatosis in mice. Hepatology 2017; 65: 813-827.
10. Rosmorduc O, Hermelin B, Boelle PY, Parc R, Taboury J, Poupon R. ABCB4 gene mutation-associated cholelithiasis in adults. Gastroenterology 2003; 125: 452-459.
11. Reichert MC, Lammert F. ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum. Semin Liver Dis 2018; 38: 299-307.
12. Condat B, Zanditenas D, Barbu V, Hauuy MP, Parfait B, El Naggar A, Collot V et al. Prevalence of low phospholipid-associated cholelithiasis in young female patients. Dig Liver Dis 2013; 45: 915-919.
13. Dixon PH, Wadsworth CA, Chambers J, Donelly J, Cooley S, Buckley R, Mannino R et al. A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol 2014; 109: 76-84.
14. Buch S, Schafmayer C, Völzke H, Becker C, Franke A, von Eller-Eberstein H, Kluck C et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet 2007; 39: 995-999.
15. Schatz SB, Jüngst C, Keitel-Anselmo V, Kubitz R, Becker C, Gerner P, Pfister ED et al. Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset. Hepatol Commun 2018; 2: 504-514.
16. Wendum D, Barbu V, Rosmorduc O, Arrivé L, Fléjou JF, Poupon R. Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations. Virchows Arch 2012; 460: 291-298.
17. Andress EJ, Nicolaou M, McGeoghan F, Linton KJ. ABCB4 missense mutations D243A, K435T, G535D, I490T, R545C, and S978P significantly impair the lipid floppase and likely predispose to secondary pathologies in the human population. Cell Mol Life Sci 2017; 74: 2513-2524.
18. Fang LJ, Wang XH, Knisely AS, Yu H, Lu Y, Liu LY, Wang JS. Chinese children with chronic intrahepatic cholestasis and high γ-glutamyl transpeptidase: clinical features and association with ABCB4 mutations. J pediatr Gastroenterol Nutr 2012; 55: 150-156.
19. Khabou B, Durand-Schneider AM, Delaunay JL, Aït-Slimane T, Barbu V, Fakhfakh F, Housset C, Maurice M. Comparison of in silico prediction and experimental assessment of ABCB4 variants identified in patients with biliary diseases. Int J Biochem Cell Biol 2017; 89: 101-109.
20. Matte U, Mourya R, Miethke A, Liu C, Kauffmann G, Moyer K, Zhang K, Bezerra JA. Analysis of gene mutations in children with cholestasis of undefined etiology. J Pediatr Gastroenterol Nutr 2010; 51: 488-493.
21. Kubitz R, Dröge C, Stindt J, Weissenberger K, Häussinger D. The bile salt export pump (BSEP) in health and disease. Clin Res Hepatol Gastroenterol 2012; 36: 536-553.
22. Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, Mieli-Vergani G, Thompson RJ. Missense mutations and single nucleotide polymorphism in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. Hepatology 2009; 49: 553-567.
23. Dexheimer P, Connor J, Karns R, Miethke A, Aronow B, Zhang K, Bezerra J. High-throughput mutation screen identifies high frequency of double and triple heterozygous gene variants in patients with idiopathic cholestasis. Presented at American Association for the Study of Liver Diseases (AASLD) 63rd Annual Meeting, Boston, MA: November 9-13, 2012. Hepatology 56(S1): 204A.
24. Goldschmidt ML, Mourya R, Connor J, Dexheimer P, Karns R, Miethke A, Sheridan R et al. Increased frequency of double and triple heterozygous gene variants in children with intrahepatic cholestasis. Hepatol Res 2016; 46: 306-311.
25. van der Woerd WL, van Haaften-Visser DY, van de Graaf SF, Férec C, Masson E, Stapelbroek JM, Bugert P et al. Mutational analysis of ATP8B1 in patients with chronic pancreatitis. PloS One 2013; 8: e80553. doi: 10.1371/journal.pone.0080553. eCollection 2013.
26. Goldstein J, Levy C. Novel and emerging therapies for cholestatic liver diseases. Liver Int 2018; 9: 1520-1535.
27. Pathak P, Liu H, Boehme S, Xie C, Krausz KW, Gonzalez F, Chiang JYL. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J Biol Chem 2017; 292: 11055-11069.
28. Keitel V, Häussinger D. Role of TGR5 (GPBAR1) in Liver Disease. Semin Liver Dis 2018; 38: 333-339.
29. Aranda V, Martinez I, Melero S, Lecanda J, Banales JM, Prieto J, Medina JF. Shared apical sorting of anion exchanger isoforms AE2a, AE21b, and AE2b2 in primary hepatocytes. Biochem Biophys Res Commun 2004; 319: 1040-1046.
30. Concepcion AR, Lopez M, Ardura-Fabregat A, Medina JF. Role of AE2 for pHi regulation in biliary epithelial cells. Front Physiol 2014; 4: 413.
31. Delaunay JL, Durand-Schneider AM, Dossier C, Falguières T, Gautherot J, Davit-Spraul A, Aït-Slimane T et al. A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3. Hepatology 2016; 63: 1620-1631.
32. Colombo C, Vajro P, Degiorgio D, Coviello DA, Costantino L, Tornillo L, Motta V et al. Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations. J Pediatr Gastroenterol Nutr 2011; 52: 73-83.
33. Johnston RC, Stephenson ML, Nageotte MP. Novel heterozygous ABCB4 gene mutation causing recurrent first-trimester intrahepatic cholestasis of pregnancy. J Perinatol 2014; 34: 711-712.
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Huynh M, Nguyen T, Grison S, Lascols O, Fernandez E, Barbu V, et all. Clinical characteristics and genetic profiles of young and adult patients with cholestatic liver disease. 6168/2019


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Publication history

Received: 10/01/2019

Accepted: 17/04/2019

Online First: 20/09/2019

Published: 03/10/2019

Article revision time: 83 days

Article Online First time: 253 days

Article editing time: 266 days


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