Identification of a compound heterozygous mutation of ABCC2 in a patient with hyperbilirubinemia

Xiang,Rong; Li,Jing‑Jing; Fan,Liang‑Liang; Jin,Jie‑Yuan; Xia,Kun; Wang,Fang

doi:10.3892/mmr.2017.6926

Identification of a compound heterozygous mutation of ABCC2 in a patient with hyperbilirubinemia

Authors:
- Rong Xiang
- Jing‑Jing Li
- Liang‑Liang Fan
- Jie‑Yuan Jin
- Kun Xia
- Fang Wang
View Affiliations

Affiliations: Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China, Department of Cellular Biology, School of Life Sciences, Central South University and State Key Laboratory of Medical Genetics, Changsha, Hunan 410013, P.R. China
Published online on: July 5, 2017 https://doi.org/10.3892/mmr.2017.6926
Pages: 2830-2834

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Bilirubin is the end product of heme catabolism, which is produced primarily from the breakdown of erythrocyte hemoglobin in the reticuloendothelial system. Hyperbilirubinemia is induced not only by increased bilirubin synthesis, but can also be caused by decreased bilirubin clearance. There are several disorders, which can contribute to hyperbilirubinemia, including Dubin‑Johnson syndrome (DJS). DJS is a rare autosomal recessive disorder, which is characterized by predominantly conjugated hyperbilirubinemia without progression to end‑stage liver disease. Previous studies have demonstrated that defects in multidrug resistance proteins ATP‑binding cassette C2 (ABCC2)/multidrug resistance‑associated protein 2 (MRP2) contribute to DJS. In the present study, a case of a patient with hyperbilirubinemia was examined and identified a compound heterozygous mutation in the ABCC2 gene (p.T435P and W442X). These were predicted to be deleterious by three bioinformatics programs (Polymorphism Phenotyping‑2, Sorting Intolerant From Tolerant and MutationTaster). These finding expand on the spectrum of ABCC2 mutations and provide additional evidence that ABCC2 is key in the development of DJS.

View Figures

View References

1	Keppler D: The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia. Drug Metab Dispos. 42:561–565. 2014. View Article : Google Scholar : PubMed/NCBI
2	Memon N, Weinberger BI, Hegyi T and Aleksunes LM: Inherited disorders of bilirubin clearance. Pediatr Res. 79:378–386. 2016. View Article : Google Scholar : PubMed/NCBI
3	Radlovic N: Hereditary hyperbilirubinemias. Srp Arh Celok Lek. 142:257–260. 2014. View Article : Google Scholar : PubMed/NCBI
4	Sticova E, Elleder M, Hulkova H, Luksan O, Sauer M, Wunschova-Moudra I, Novotny J and Jirsa M: Dubin-Johnson syndrome coinciding with colon cancer and atherosclerosis. World J Gastroenterol. 19:946–950. 2013. View Article : Google Scholar : PubMed/NCBI
5	Uchiumi T, Tanamachi H, Kuchiwaki K, Kajita M, Matsumoto S, Yagi M, Kanki T and Kang D: Mutation and functional analysis of ABCC2/multidrug resistance protein 2 in a Japanese patient with Dubin-Johnson syndrome. Hepatol Res. 43:569–575. 2013. View Article : Google Scholar : PubMed/NCBI
6	Li P, Wang Y, Zhang J, Geng M and Li Z: Dubin-Johnson syndrome with multiple liver cavernous hemangiomas: Report of a familial case. Int J Clin Exp Pathol. 6:2636–2639. 2013.PubMed/NCBI
7	Chen ZS and Tiwari AK: Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases. FEBS J. 278:3226–3245. 2011. View Article : Google Scholar : PubMed/NCBI
8	Sticova E and Jirsa M: New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol. 19:6398–6407. 2013. View Article : Google Scholar : PubMed/NCBI
9	Xiang R, Fan LL, Huang H, Cao BB, Li XP, Peng DQ and Xia K: A novel mutation of GATA4 (K319E) is responsible for familial atrial septal defect and pulmonary valve stenosis. Gene. 534:320–323. 2014. View Article : Google Scholar : PubMed/NCBI
10	Sunyaev S, Ramensky V and Bork P: Towards a structural basis of human non-synonymous single nucleotide polymorphisms. Trends Genet. 16:198–200. 2000. View Article : Google Scholar : PubMed/NCBI
11	Ng PC and Henikoff S: SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 31:3812–3814. 2003. View Article : Google Scholar : PubMed/NCBI
12	Schwarz JM, Rödelsperger C, Schuelke M and Seelow D: MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 7:575–576. 2010. View Article : Google Scholar : PubMed/NCBI
13	Fujiwara R, Maruo Y, Chen S and Tukey RH: Role of extrahepatic UDP-glucuronosyltransferase 1A1: Advances in understanding breast milk-induced neonatal hyperbilirubinemia. Toxicol Appl Pharmacol. 289:124–132. 2015. View Article : Google Scholar : PubMed/NCBI
14	Christensen RD and Yaish HM: Hemolytic disorders causing severe neonatal hyperbilirubinemia. Clin Perinatol. 42:515–527. 2015. View Article : Google Scholar : PubMed/NCBI
15	Emi Y, Yasuda Y and Sakaguchi M: A cis-acting five-amino-acid motif controls targeting of ABCC2 to the apical plasma membrane domain. J Cell Sci. 125:3133–3143. 2012. View Article : Google Scholar : PubMed/NCBI
16	Okada H, Kusaka T, Fuke N, Kunikata J, Kondo S, Iwase T, Nan W, Hirota T, Ieiri I and Itoh S: Neonatal Dubin-Johnson syndrome: Novel compound heterozygous mutation in the ABCC2 gene. Pediatr Int. 56:e62–e64. 2014. View Article : Google Scholar : PubMed/NCBI
17	Devgun MS, El-Nujumi AM, O'Dowd GJ, Barbu V and Poupon R: Novel mutations in the Dubin-Johnson syndrome gene ABCC2/MRP2 and associated biochemical changes. Ann Clin Biochem. 49:609–612. 2012. View Article : Google Scholar : PubMed/NCBI
18	Lee JH, Chen HL, Chen HL, Ni YH, Hsu HY and Chang MH: Neonatal Dubin-Johnson syndrome: Long-term follow-up and MRP2 mutations study. Pediatr Res. 59:584–589. 2006. View Article : Google Scholar : PubMed/NCBI
19	Kruer MC, Jepperson T, Dutta S, Steiner RD, Cottenie E, Sanford L, Merkens M, Russman BS, Blasco PA, Fan G, et al: Mutations in gamma adducin are associated with inherited cerebral palsy. Ann Neurol. 74:805–814. 2013. View Article : Google Scholar : PubMed/NCBI
20	Kaufmann KB, Büning H, Galy A, Schambach A and Grez M: Gene therapy on the move. EMBO Mol Med. 5:1642–1661. 2013. View Article : Google Scholar : PubMed/NCBI
21	van Dijk R, Beuers U and Bosma PJ: Gene replacement therapy for genetic hepatocellular jaundice. Clin Rev Allergy Immunol. 48:243–253. 2015. View Article : Google Scholar : PubMed/NCBI
22	Stapelbroek JM, van Erpecum KJ, Klomp LW and Houwen RH: Liver disease associated with canalicular transport defects: Current and future therapies. J Hepatol. 52:258–271. 2010. View Article : Google Scholar : PubMed/NCBI