international ELSEVIER
Hepatology Communications 5 (1996) 297-307
Mini review
Genetic background of constitutional unconjugated hyperbihbinemia Yukihiko “Second
Adachi”,*, Toshinori Kamisakoa, Osamu Koiwaib, Kazuo Yamamotoc, Hiroshi Sated
Department
of Internal
Kinki Univewity, School of‘ Medicine, Osakasuyamn, Osaka 589, Japan bDepartment of Biochemistry, Aichi Cancer Cenrer Research Institute, Nagoya 464, Japan “Second Department of internal Medicine, Shiga Umoersity of Medical Science, Otsu 520-21. Jnpnn “Department uf Biology,Shigu University of’ Medical Science, Otsu 520-21, Japan Received
Medicine,
17 April
1996; revised
5 July
1996; accepted
12 July
1496
Abstract Crigler-Najjar syndrome (types I and 11) and Gilbert’s syndrome are fannlial disorders associated with severe to mild unconjugated hyperbilirubinemia. In these conditions, the activity of bilirubin UDP-glucuronosyltransferase (UGTI * l), which is located in the hepatocyte endoplasmic reticulum, is defective, and severely and moderately decreased, respectively. UGTl*l is derived from one of the UGTl genes. It has a promoter containing a TATA box and consists of exon 1A (which is one of the individual first exons) and common exons 2-5. UGTl*l mRNA is formed by differential splicmg of these exons. In recent years, gene analysis of these syndromes has been carried out, and genetic abnormalities have been clarified. Homozygous nonsense mutations, mis-sense mutations, and other relevant mutations of exons lA-5 have been reported in almost all of the patients with Crigler-Najjar syndrome type I, while mainly homozygous mls-sense mutations of exons IA, 2, and 5 have been reported in type II patients. Almost all patients with this syndrome (types I and II) show autosomal recessive inheritance. On the other hand, some patients with Gilbert’s syndrome show hererozygous mis-sense mutations in exons IA, 4, and 5, while others show
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homozygous 2-base pair-insertion mutation (TA) into the TATA box in the promoter region [A(TA),TAA; normal: A(TA),TAA]. The pattern of inheritance can be autosomal recessive or autosomal dominant. It has also been clarified that enzyme activity is lowered to about 30% (rather than 50%) by heterozygous mutations of the coding region. because of the occurrence of dominant negative mutation based on subunit-structure of the enzyme. Keywords: Crigler-Najjar ferase; Heredity
syndrome;
Gilbert’s
syndrome; Gunn rat; UDP-glucuronosyltrans-
It is known that the enzymatic activity of bilirubin UDP-glucuronosyltransferase (bilirubin UGT: UGTl*l [l]) shows a moderate and a marked decrease in Gilbert’s syndrome and Crigler-Najjar syndrome type II, respectively, while it is absent in Crigler-Najjar syndrome type I [2]. In recent years, the UGTl gene has been mapped and a number of reports have been published on gene mutations in these syndromes. These reports are reviewed briefly in the present paper. After incorporation into hepatocytes, bilirubin may be bound to ligandin [3] or may rapidly pass through the membranous structures of the cytoplasm [4,5] to reach the endoplasmic reticulum. The mechanism involved in bilirubin transport to the lumen of the endoplasmic reticulum is still unclear. In the lumen, bilirubin receives glucuronic acid from UDP glucuronic acid (UDPGA) in a reaction catalyzed by UGTl *l, after which two propionic acid groups undergo ester conjugation to form bilirubin monoglucuronide (BMG) and then bilirubin diglucuronide (BDG) (both are called conjugated bilirubin). In healthy individuals, most bilirubin is conjugated to BDG [6]. During conjugation, glucose and xylose are also respectively received from UDP glucose (UDPG) and UDP xylose, with the process dependent on UGTl*l [6]. UGT is divided into two groups of enzymes (UGTl and UGT2). The former group is mainly involved in the glucuronic acid conjugation of bilirubin, phenols, and quaternary ammonium, while the latter group plays an important role in the conjugation of bile acids, steroids, and odorant substances. Both groups are essential for normal biliary excretion of these substances [1,6]. In human, the UGTl gene is located on chromosome 2q37 [7] (chromosome 9q35 to q36 [8] in rats), while the UGT2 gene is found on chromosome 4 [9] (chromosome 14 in rats [lo]). UGTl has a sugar chain and a molecular weight of 48-56 kDa. It is divided into three portions: a small portion found in the cytoplasm, a portion that passes through the endoplasmic reticulum membrane, and the active portion inside the lumen of the endoplasmic reticulum [ll]. The UGTl gene consists of 5 exons: the N-terminal exon 1 is different in each isozyme and is substrate-specific (there are at least seven kinds labeled from 1A to lG), while the carboxy-terminal common exons 225 code for binding to the endoplasmic reticulum, passage through the membrane, and binding to UDPGA. There is a promoter area in the upstream of each exon 1 [1,6,12] (Fig. 1). The UGTl gene complex of rats as well as that of humans consists of various first exons and the carboxy-terminal common exons (described below). Human bilirubin UGT is the enzyme UGTl*l derived
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from exons 1A and 2-5 [13]. UGTI *l, which conjugates bilirubin to BDG, is reported to form a tetramer [14,15] and may be concerned with the glucuronidation of estriol, estradiol, ethynylestradiol [16], thyroxine (T4), 3,3’,5’-triiodo L-thyronine (reverse T3) [17], and opioids [18] in addition to that of bilirubin and BMG. Exons 1F and 1G code for the peptides recognizing planar phenols (such as 1-naphthol) [19] and bulky phenols [20], respectively, while exon 1D codes for the peptide recognizing quaternary ammonium compounds [21]. UGT1*6. UGT1*7, and UGT1*4 are respectively produced by these exons. The substrates of other exon 1 subtypes are still obscure and the physiological significance of other UGTl isozymes has not yet been elucidated. Studies of enzyme or mRNA induction in rats have shown that 3-methylcholanthrene induces phenol UGTs, while phenobarbital, clofibrate, and dexamethasone induce bilirnbin UGT [6,22,23]. It has been reported that the presence of a xenobiotic responsive element (-134 to -129 TGCGTG) within the UGTlAl promoter, is essential for the induction of phenol UGT (UGTlAl) by 3-methylcholanthrene in rats [24]. 3,5,3’-Triiodo L-thyronine (T3) also induces phenol UGTs, while it inhibits bilirubin UGT production [25]. The common substrate UDPGA is produced from UDPG by UDPG dehydrogenase within the cytoplasm and is transported into the lumen of the endoplasmic reticulum by a carrier protein located on the reticulum membrane. Berg et al. [26] and Bossuyt et al. [27] have reported that UDPGA transport increases and becomes saturated in a temperature-dependent manner, while it is inhibited by 4,4’-diisothiocyanatostilbene-2,2’-disulfonic acid (an anion transport inhibitor) and shows cis-inhibition and trans-stimulation by UDP-N-acetylglucosamine. Thus, this transport process was concluded to represent energy-independent carrier-mediated transport. UDPG is also transported across the membrane of the endoplasmic reticulum. Conjugated bilirubin is considered to pass through the membrane of the endoplasmic reticulum again and is bound to ligandin within the cytoplasm. However, the binding constant of ligandin for BDG is about one-fifth that for unconjugated bilirubin [28]. Hydrophilic conjugated bilirubin may be transported across the endoplasmic reticulum by a carrier protein which is different from that involved in 1-naphthol glucuronide excretion into urine (secretion into blood) [29]. Abnormalities of the UGTl gene were first detected in Gunn rats, which were studied as a model of Crigler-Najjar syndrome type I. Based on the results of cDNA analysis of methylcholanthrene-inducible UGT (phenol UGT), Iyanagi et al. [30,31] concluded that a -1 frame shift mutation was caused by homozygous separation of the 1239th (or 1240th) nucleotide (G). This formed a stop codon that led to the production of a truncated enzyme lacking 115 amino acids from the 415th on the COOH side, resulting in loss of anchoring of the enzyme to the endoplasmic reticulum. More recently, Sato et al. [32,33] isolated bilirubin UGT cDNA and demonstrated that 4-nitrophenol UGT and bilirubin UGT were derived from a single gene by differential splicing and that jaundice in Gunn rats was due to an abnormality of bilirubin UGT, because the 3’-halves of 4-nitrophenol UGT and bilirubin UGT cDNA have the same sequence. The cDNA of bilirubin UGT, which consists of 1763 bp, showed a -1 frame shift mutation at the same site as that of 4-nitrophenol UGT reported by Iyanagi et al., and both enzymes had a splicing
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consensus sequence at the site where the common sequence started. Subsequently, Iyanagi [34] separated three kinds of UGT in Gunn rats using the mutant cDNA of 4-nitrophenol UGT as a probe. They found that 1362 base pairs, including a monobasic deletion at the same site, corresponded with the cDNA of 4-nitrophenol UGT on the 3’-side, while there was less than 40% homology [30] on the S-side encoding the substrate-bound domain. They also described the formation of mRNAs for UGTl isozymes by differential splicing between the substrate-specific 5’-side exons and the common 3’-side exons. In humans, over 20 patients with Crigler-Najjar syndrome type I (liver bilirubin UGT activity is completely absent and serum bilirubin levels are usually over 340 ymol/l) have so far been reported in whom homozygous base pair deletion was associated with frame shift mutation, nonsense mutation, mis-sense mutation, or insertion mutation in all exons IA-5 of the UGTl*l gene complex [35-431. The only exception was one compound heterozygote which had a Cysl77Arg in exon 1A and a 14-bp deletion combined with a frame shift mutation in exon 2 [44] (Fig. 2). Almost all of these patients show autosomal recessive inheritance and bilirubin UGT activity does not develop when the abnormal gene is introduced into COS cells [35,36,44}. In Japan, four patients from three families have undergone UGTl*l gene analysis. A homozygous nonsense mutation of Cys280Stop in exon UGT7
Promoter
Gene Complex
g....
3’ 1G
1F
1E
1D
%I
1C
1B
1A
234
5
/
Y
First Exons
Exons
mRNA --m&j1G
* 2-5
1F
2-5
Phenol UGTs (UGTlt7,lX6) Bilirubin
1D
2-5
1A
Quatematy Ammonium UGT (UGT 1x4)
2-5
Bilirubin UGT (UGT it 1)
UGTfEnzyme) K-
285
a.a. -
246 a.a.
NH2
COOH
Substrate-Binding Domein
\-,-’ UDPGABinding Domein
Membrane Anchoring Domein
Fig. 1. Gene complex, messenger RNA, and enzyme of UGTl. The UGTl gene complex is composed of multiple first exons and the common exons 2-5. The messenger RNA (mRNA) for each isozyme of UGTl is formed by differential splicing of the various first exons with the common exons. In the middle of the figure, the mRNAs for UGTl*l. UGTl*4, UGTl*6, and UGTl*7 are shown. The UGTl*l enzyme is shown at the bottom of the figure.
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Promoter (TATA Box) Phel70 deletion# Cysl77Arg* a Gly276Arg# CysPSOStop# Exon 2 deletion# 72 aa unrelated AUiJ;;w$ssing# Gly308Glu# Glt-1331 Stop# & Exon 2 skipping Frame Shift* a
Exon 1A
Exon 2
Trp335Stop# c d Arg341 Stop# Gln357Stop# e Gln357Arg’
Ser375Phe# Ser381 Arg# Ala401 Thr# c Ala401 Pro# e f Lys426Glu# b Frame Shift# d
Exon 3
Exon 4
Lys437Stop*
e
Exon 5
Fig. 2. Reported mutations of UGTl gene in Crigler-Najjar syndrome type I. Homozygous mutations of the coding region have been reported in all but one patient. The promoter and the exons are not precisely scaled (same in Figs. 3 and 4). # , Homozygote; *. heterozygote; a-e combined mutations indicated by each letter; f without combined mutation.
1A was noted in all of them and their ancestors were all from the Mikawa District [37,45]. This report suggested the role of geographic factors in establishment of the gene abnormality of UGTl. In patients with Crigler-Najjar syndrome type IT, serum bilirubin levels are usually 102-340 umol/l and the mean bilirubin UGT activity is decreased to about 10% of that in healthy individuals [46]. Four of these patients [44,47-491 have been
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reported to show homozygous mis-sense mutations in UGTl * 1 gene complex exon lA, 2, or 5, while one patient had a heterozygous mis-sense mutation and a single nucleotide deletion in exon 1A and exon 2 [44], respectively, and one patient had a heterozygous nonsense mutation in exon 2 [50] (Fig. 3). Thus, most of the type II patients show autosomal recessive inheritance. In patients with Gilbert’s syndrome, serum bilirubin levels are usually 17-102 umol/l and the mean level of enzyme activity is decreased to about 30% of that in healthy individuals [46]. There are reports on patients with heterozygous [15] or occasionally homozygous mis-sense mutations [51] in exons 1A and 4 of the UGTl* 1 gene complex and patients with a homozygous 2-bp insertion [TATA box: A(TA),TAA; normal: A(TA),TAA] [52,53]. Our further studies have shown the presence of patients with heterozygous (sometimes homozygous) mis-sense muta5’ Promoter
(TATA Box)
Gly71 Arg# a Leul75 Glu* b Arg209Trp#
Gln331Arg# Gln331 Stop* Frame Shift *
Tyr466A&
Exon 1 A
Exon 2
b
a
Exon 5
Fig. 3. Reported mutations of UGTl gene in Crigler-Najjar syndrome type II. Three patients with homozygous mis-sense mutations, one patient with combined heterozygous mutations in exons 1A and 2, and one patient with a heterozygous nonsense mutation in exon 2 have been reported. #, Homozygote; *, heterozygote; a,b combined mutations in two patients each with the same letter.
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A (TA),TAA#
Gly71Ar9* Pro229Gln*
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Box)
1A
Exon
2
Exon
3
Arg367Gly*
Exon
4
Tyr496Asp*
Exon
5
Fig. 4. Reported mutations of UGTl gene in Gilbert’s syndrome. Two types of mutations have been reported. One is a 2-base pair insertion in the promoter region [A(TA),TAA; normal: A(TA),TAA], and the other is a heterozygous (sometimes homozygous) mis-sense mutation in the coding region. #, Homozygote; *, heterozygote.
tions and patients with a homozygous 2-bp insertion [54] (Fig. 4). Thus, patients with a homozygous mis-sense mutation of the coding region do not necessarily have Crigler--Najjar syndrome type II and serum bilirubin levels may remain within the range for Gilbert’s syndrome in some of them. If a heterozygous mis-sense mutation is present, bilirubin UGT activity should be more than 50%. According to Koiwai et al. [55], enzymatic activity showed a marked decrease (25% of the normal level) when Pro229Gln, an abnormal gene, was introduced into COS cells together with the same amount of the normal gene, indicating the possibility of a dominant negative mutation (Fig. 5). A similar marked decrease of enzymatic activity (6% of the normal level) was also observed when equal amounts of an abnormal gene (Gln331Stop) from a patient with heterozygous Crigler-Najjar syndrome type II and the normal gene were co-transfected into COS cells [50]. Bosma et al. [52] reported that six family members of a Crigler-Najar syndrome type II patient with heterozygous mis-sense mutation in the coding region (Arg209Trp) [47] showed normal serum bilirubin level. The
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reported mutation is different from those found in patients with Gilbert’s syndrome. This indicates that this mutation is irrelevant to the pathogenesis of Gilbert’s syndrome in the heterozygous state probably because of a weak effect of the mutation on the enzyme activity or of impossibility of assembly of monomers into terramers as shown in the bottom panel of Fig. 5. They also reported that the development of luciferase activity was much lower when the firefly luciferase gene with a promoter containing A(TA),TAA in the upstream of the 5’ side was introduced into human hepatoma cell line than when a normal promoter was used [52]. However, since homozygous TATA box mutation is also noted in healthy individuals [52,53], this mutation may not always cause Gilbert’s syndrome, and the existence of other factors, such as occult hemolysis and fasting, must also be taken into consideration [56]. Thus, it may be concluded that patients with Gilbert’s syndrome may show either autosomal recessive or dominant inheritance. Since the gene abnormalities in constitutional unconjugated hyperbilirubinemia have been clarified as described above, in vivo studies involving gene introduction into Gunn rat hepatocytes using vectors such as retrovirus have been commenced for the purpose of developing gene therapy for Crigler-Najjar syndrome type I, which is characterized by a high mortality rate from kernicterus in infants. Recent excellent reviews on this subject are available [57,58].
l/16
l/l6
(population)
Failed assembly of mutated monomers
(population)
Fig. 5. Diagram showing dominant negative mutation of the bilirubin UGT gene. Assembly of enzyme monomers into tetramers is shown in the top panel. In the presence of mutant monomers from a heterozygous mutation, only l/16 of the assembled tetramers are completely intact (middle panel). Bilirubin UGT activity therefore depends on the activity of the remaining tetramers containing mutant monomers (ranging from about 30% in Gilbert’s syndrome to about 10% in Crigler-Najjar syndrome type II). If the mutant monomers cannot assemble into tetramers because of severe conformational changes, the tetramers produced are all intact resulting in about 50% of the normal enzyme activity, which may not cause jaundice (bottom panel).
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References [I] Burcheli B. Nebert DW, Nelson DR, et al. The UDP glucuronosyltransferase gene superfamily: suggested nomenclature based on evolutionary divergence. DNA Cell Biol 1991; 10: 487-494. [2] Isselbacher KJ. Bilirubin metabolism and hyperbilirubinemia. In: Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, eds. Harrison’s principles of internal medicine, 13th edn. New York: McGraw-Hill, 1994; 1453-1458. [3] Wolkoff A, Goresky CA, Sellin J, Gatmaitan Z, Arias IM. Role of ligandin in transfer of bilirubin from plasma into liver. Am J Physiol 1979; 26: E6388E648. [4] Whitmer DI, Russell P, Gollan JL. Membrane-membrane interactions associated with rapid transfer of liposomal bilirubin to microsomal UDP-glucuronyl-transferase. Relevance for hepatocellular transport and biotransformation of hydrophobic substrates. Biochem J 1987; 244: 41-47. [5] Zucker SD, Goessling W, Ransil BJ, Gollan JL. Influence of glutathione S-transferase B (ligandin) on the intermembrane transfer of bilirubin. J Clin Invest 1995; 96: 1927- 1935. [6] Burchell B, Coughtrie MWH, Jansen PLM. Function and regulation of UDP-glucuronosyltransferase genes in health and liver disease: report of the Seventh International Workshop on Glucuronidation, September 1993, Pitlochry, Scotland. Hepatology 1994; 20: 1622-1630. [7] Van Es HHG, Bout A, Liu J. et al. Assignment of the human UDP-glucuronosyltransferase gene (UGTlal) to chromosome 2q7. Cytogenet Cell Genet 1993; 63: I14- 116. [8] Nagai F. Satoh H, Mori S, et al. Mapping of rat bilirubin UDP-glucuronosyltransferase gene (Ugt la1 ) to chromosome region 9q35-q36. Cytogenet Cell Genet 1995; 69: 1855 186. [9] Monaghan G, Povey S. Burchell B, Boxer M. Localization of a bile acid UDP-glucuronosyltransferase gene (UGT2B) to chromosome 4 using the polymerase chain reaction. Genomics 1992; 13: 908-909. [lo] Satoh H, Nagai F, Homma H, Mori S, Matsui M. Regional assignment of rat androsterone UDP-glucuronosyltransferase gene (UGT2B2) to chromosome 14p21.2-~22. Cytogenet Cell Genet 1993; 62: 49-51. [ll] Shepherd SRP, Baird SJ, Hallinan T, Burchell B. An investigation of the transverse topology of bilirubin UDP-glucuronosyltransferase in rat hepatic endoplasmic reticulum. Biochem J 1989; 259: 617-620. [12] Owens IS, Ritter JK. The novel bilirubin/phenol UDP-glucuronosyltransferase UGTl gene locus: implications for multiple nonhemolytic familial hyperbilirubinemia. Pharmacogenetics 1992; 2: 93m108. [13] Bosma PJ, Seppen J, Goldhoorn B. Bilirubin UDP- glucuronosyltransferase I is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem 1994; 269: 17 960-17 964. [14] Peters WHM, Jansen PLM, Nauto H. The molecular weights of UDP-glucuronosyltransferase determined with radiation-inactivation analysis. J Biol Chem 1984; 259: 11 701-l 1 705. [15] Aono S, Adachi Y, Uyama E, et al. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert’s syndrome. Lancet 1995; 345: 958-959. [16] Senafi SB. Clarke DJ, Burchell B. Investigation of the substrate specificity of a cloned expressed human bilirubin UDP-glucuronosyltransferase: UDP-sugar specificity and involvement in steroid and xenobiotic glucuronidation. Biochem J 1994; 303: 233-240. [17] Visser TJ. Kaptein E, Gijzel AL, De Herder WW, Ebner R, Burchell B. Glucuronidation of thyroid hormone by human bilirubin and phenol UDP-glucuronosyltransferase isozymes. FEBS Lett 1993; 324: 3588360. [18] Coffman BL, Green MD, King CD. Tephly TR. Cloning and stable expression of a cDNA encoding a rat liver UDP-glucuronosyltransferase (UDP-glucuronosyltransferase 1.1) that catalyzes the glucuronidation of opioids and bilirubin. Mol Pharmacol 1995: 47: 1101-l 105. [19] Harding D, Fournel-Gigleuz S, Jackson MR. Burchell B. Cloning and substrate specificity of a human phenol UDP-glucuronosyltransferase expressed in COS-7 cells. Proc Nat1 Acad Sci USA 1988; 85: 8381-8385. [20] Wooster R, Sutherland L, Ebner T, et al. Cloning and stable expression of a new member of the human liver phenol/bilirubin: UDP-glucuronosyltransferase cDNA family. Biochem J 1991; 278: 465-469.
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