A Splice Mutation in the Human Canalicular Multispecific Organic Anion Transporter Gene Causes Dubin-Johnson Syndrome

doi:10.1006/bbrc.1998.9780

Biochemical and Biophysical Research Communications

Volume 253, Issue 2, 18 December 1998, Pages 454-457

https://doi.org/10.1006/bbrc.1998.9780 Get rights and content

Abstract

The human Dubin Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by chronic conjugated hyperbilirubinemia and impaired hepatobiliary transport of non-bile salt organic anions. A highly homologous phenotype exists in the transport deficient (TR−) Wistar rat, which has a defective canalicular multispecific organic anion transporter (cMOAT). This protein mediates adenosine triphosphate-dependent transport of a broad range of endogenous and xenobiotic compounds across the (apical) canalicular membrane of the hepatocyte. The cDNA encoding ratcMOAThas recently been cloned, and this mutation in the TR− rat has been identified. Subsequently the human homologue of ratcMOATlocalized in the liver was found to be the cause of DJS. In an individual with DJS, we have identified a single novel nucleotide substitution in the exon-intron junction of thecMOATgene which generates liver cDNA with a 67bp exon deletion.

References (16)

P. Chomczynski et al.
Anal. Biochem.
(1987)
I.N. Dubin et al.
Medicine
(1954)
Y. Adachi et al.
Nihon Rinsyou
(1992)
C.C. Paulusma et al.
Science
(1996)
K. Taniguchi et al.
Cancer Res.
(1996)
D. Keppler et al.
FASEB J.
(1997)
C.C. Paulusma et al.
Hepatology
(1997)

There are more references available in the full text version of this article.

Cited by (66)

Bile pigment metabolism and its disorders
2019, Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics: Cardiovascular, Respiratory, and Gastrointestinal Disorders
Bilirubin is the breakdown product of the heme moiety of hemoproteins, including hemoglobin, myoglobin, and several hepatic hemoproteins. About 80% of the 200–300 mg bilirubin is produced daily in reticuloendothelial cells from hemoglobin of senescent erythrocytes, the remainder being derived mostly from hepatic hemoproteins. Microsomal heme oxygenases cleave heme forming biliverdin, which is reduced to bilirubin by biliverdin reductase. At low concentrations, bilirubin is cytoprotective and provides metabolic benefits. However, bilirubin-induced neurological damage (BIND) caused by severe unconjugated hyperbilirubinemia is a major clinical concern. Physiologically, BIND is prevented by binding to plasma albumin, rapid uptake by hepatocytes, UGT1A1-mediated glucuronidation, and active canalicular excretion. A fraction of the bilirubin glucuronides is pumped out by ABCC3 through the sinusoidal surface of hepatocytes and undergoes reuptake by hepatocytes located downstream to sinusoidal blood flow. A small portion of bilirubin excreted in bile undergoes enterohepatic recycling, the remainder being degraded by bacteria to urobilinogen. Unconjugated hyperbilirubinemia can be caused by excessive bilirubin production, reduced hepatocellular uptake, or defective glucuronidation, whereas conjugated hyperbilirubinemia results from defective canalicular excretion or abnormal reuptake. Hyperbilirubinemia, which is universal in neonates, normally resolves in 1–2 weeks, but can be exacerbated or prolonged by breastfeeding or delayed UGT1A1 maturation (Lucey–Driscoll syndrome). In addition to acquired hepatobiliary diseases and hemolysis, a number of inherited liver disorders can cause lifelong hyperbilirubinemia. Coding region mutations of UGT1A1 can cause complete or partial loss of bilirubin glucuronidation (Crigler–Najjar syndrome, type 1 and type 2, respectively). A variant UGT1A1 promoter can reduce UGT1A1 expression, causing mild and innocuous unconjugated hyperbilirubinemia (Gilbert syndrome). Conjugated hyperbilirubinemia can result from mutations of the ABCC2 that reduce canalicular secretion of bilirubin glucuronides and many other organic anions causing Dubin–Johnson syndrome. Concurrent mutations of ABCB1 and ABCB3 disable reuptake of bilirubin glucuronides, causing mild conjugated hyperbilirubinemia (Rotor syndrome). Several other inherited defects of bile canalicular proteins cause four types of progressive familial intrahepatic cholestasis that cause mixed hyperbilirubinemia as well as liver injury.
Clinical, Pathologic, and Genetic Features of Neonatal Dubin-Johnson Syndrome: A Multicenter Study in Japan
2018, Journal of Pediatrics
Citation Excerpt :
Two novel variants were identified (c.351_355dup and c.1354_1357del), and 6 variants were reported in our previous study13: R100Ter, c.1815+2T>A, c.1967+2T>C, R768W, c.2439+2T>C, and K961R (Table III; available at www.jpeds.com). Six variants (R100Ter, R393W, c.1815+2T>A, c.1967+2T>C, c.2439+2T>C, and R1310Ter) have been reported in adolescent or adult patients with Dubin-Johnson syndrome.16-20 Two variants (W709R and R768W) have been reported in patients with neonatal Dubin-Johnson syndrome (Figure 3; available at www.jpeds.com).8,21
To clarify the clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome.
Ten patients with neonatal Dubin-Johnson syndrome were recruited from 6 pediatric centers in Japan between September 2013 and October 2016. Clinical and laboratory course, macroscopic and microscopic liver findings, and molecular genetic findings concerning ATP-binding cassette subfamily C member 2 (ABCC2) were retrospectively and prospectively examined.
All neonates exhibited cholestasis, evident as prolonged jaundice with or without acholic stools and elevations of serum direct bilirubin as well as γ-glutamyltransferase or total bile acids. Only 38% (3 of 8) of patients who underwent liver biopsy showed a grossly black liver or melanin-like pigment deposits in hepatocytes; their biopsies were performed in early infancy. Immunohistochemically, all liver specimens showed no expression of multidrug resistance-associated protein 2 but increased expression of the bile salt export pump protein. Homozygous or compound heterozygous pathogenic variants of ABCC2 were identified in all patients, representing 11 distinct pathogenic variants including 2 not previously reported.
Immunohistochemical staining of the liver for multidrug resistance-associated protein 2 and molecular genetic analysis of ABCC2 are crucial for accurate diagnosis of neonatal Dubin-Johnson syndrome.
Efflux Transporters
2018, Comprehensive Toxicology: Third Edition
Discovery of the ATP-binding cassette (ABC) superfamily of membrane transporters has opened up a new chapter in understanding the absorption, distribution, and elimination of xenobiotics. These ABC transporters mediate the ATP-dependent efflux of endo- and xenobiotics from cells into the external environment (such as efflux from enterocytes into the intestinal lumen), or into blood or interstitial fluid, and are thus known to be important in protecting the cell and organism from toxic environmental compounds, including toxic agents used in cancer chemotherapy. These transporters also mediate the efflux of signaling molecules, such as cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and prostaglandins (PGs), and at least one transporter functions in the efflux of vitamins into breast milk. Thus, their role in endogenous processes is also likely critical. This article describes the expression, regulation, and functions of some of the most important ABC transporters in influencing exposure to xenobiotics and regulating intracellular levels of important endogenous compounds.
Bile Pigment Metabolism and Its Disorders
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Efflux Transporters
2010, Comprehensive Toxicology, Second Edition
Discovery of the ATP-binding cassette (ABC) superfamily of membrane transporters has opened up a new chapter in understanding the absorption, distribution, and elimination of xenobiotics. These ABC transporters mediate the ATP-dependent efflux of endo- and xenobiotics from cells into the external environment (such as efflux from enterocytes into the intestinal lumen), or into blood or interstitial fluid, and are thus known to be important in protecting the cell and organism from toxic environmental compounds, including toxic agents used in cancer chemotherapy. These transporters also mediate the efflux of signaling molecules, such as cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and prostaglandins (PGs), and at least one transporter functions in the efflux of vitamins into breast milk. Thus, their role in endogenous processes is also likely critical. The following chapter describes the expression, regulation, and functions of some of the most important ABC transporters in influencing exposure to xenobiotics and regulating intracellular levels of important endogenous compounds.
Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia–A narrative review
2022, United European Gastroenterology Journal

View all citing articles on Scopus

^☆: Abbreviations used: DJS, Dubin-Johnson syndrome; CMOAT, canalicular multispecific organic anion transporter

¹: Address for correspondence: Susumu Kajihara M.D., Ph.D., Division of Metabolism and Endocrinology, Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan. Fax: 81-11-952-34-2017. E-mail:[email protected].

View full text

Regular ArticleA Splice Mutation in the Human Canalicular Multispecific Organic Anion Transporter Gene Causes Dubin-Johnson Syndrome☆

Abstract

Anal. Biochem.

Medicine

Nihon Rinsyou

Science

Cancer Res.

FASEB J.

Hepatology

Regular Article
A Splice Mutation in the Human Canalicular Multispecific Organic Anion Transporter Gene Causes Dubin-Johnson Syndrome☆