Molecular Diagnostics of Hereditary Unconjugated Hyperbilirubinemias in Slovakia


Authors: I. Zmetáková;  I. Čierna;  D. Székyová;  G. Minárik;  A. Ficek;  H. Poláková;  V. Ferák;  E. Feráková;  Ľ. Kádaši;  L. Kovács
Authors‘ workplace: Katedra molekulovej biológie Prírodovedeckej fakulty UK v Bratislave a Ústav molekulárnej fyziológie a genetiky SAV, Bratislava vedúci doc. RNDr. Ľ. Kádaši, DrSc. ;  2. detská klinika Lekárskej fakulty Univerzity Komenského a Detskej fakultnej nemocnice, Bratislava prednosta prof. MUDr. L. Kovács, DrSc., MPH
Published in: Čes-slov Pediat 2009; 64 (5): 223-229.
Category: Original Papers

Overview

Known forms of hereditary unconjugated hyperbilirubinemias are symptomatically and prognostically diverse defects of bilirubin metabolism caused by various alterations of the UGT1 gene, which codes for the enzyme uridine diphosphoglucuronosyl transferase. The aim of the present work was to determine the spectrum of molecular alterations that contribute to their development in Slovak population.

Patients and methods:
Presence of insertion A(TA)7TAA and substitution T-3279G in the regulating areas of the UGT1A1 gene was determined in DNA samples from 110 unrelated subjects with clinically diagnosed Gilbert’s syndrome and from 240 clinically asymptomatic Slovak control subjects of both Gypsy and Non-Gypsy origin (120 and 120 subjects). In addition to this, mutation analysis of the UGT1A1 gene was accomplished in two unrelated Slovak kindreds with clinically diagnosed Crigler-Najjar syndrome type I.

Results:
101 of 110 (91.8%) patients with Gilbert’s syndrome were homozygotes for both the insertional A(TA)7TAA as well as the substitutional T-3279G polymorphism detected in the UGT1A1 gene (allelic frequency 0.95). The allelic frequency of the A(TA)7TAA polymorphism was identical (q = 0.36 and p = 0.64) in control subjects of both Gypsy and Non-Gypsy origin that corresponds in this population to an expected frequency of homozygotes for A(TA)7TAA insertion of 12.9 %. In one of the two unrelated Slovak kindreds with Crigler-Najjar syndrome type I we found a homozygous deletion 1220delA in exon 4 of the UGT1A1 gene (kindred A). Affected subjects from kindred B carried two different deletions (717-718delAG in exon 1 and 1220delA in exon 4) in gene UGT1A1.

Conclusion:
Available molecular analysis of the UGT1A1 gene has an important role for exact clinical diagnosis of Gilbert’s syndrome and contributed to prenatal diagnosis of Criegler-Najjar syndrome in affected kindreds.

Key words:
hereditary unconjugated hyperbilirubinemias, Gilbert’s syndrome, Criegler-Najjar syndrome, genetics


Sources

1. Ando Y, Chida M, Nakayama K, Saka H, Kamataki T. The UGT1A1*28 allele is relatively rare in a Japanese population. Pharmacogenetics 1998;8: 357–360.

2. Arias IM, Gartner LM, Cohen M, Ezzer JB, Levi AJ. Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency. Clinical, biochemical, pharmacologic and genetic evidence for heterogeneity. Am. J. Med. 1969;47: 395–409.

3. Arias IM, Gartner LM, Seifter S, Furman M. Prolonged neonatal unconjugated hyperbilirubinemia associated with breast feeding and a steroid, pregnane-3 (alpha), 20(beta)-diol, in maternal milk that inhibits glucuronide formation in vitro. J. Clin. Invest. 1964;43: 2037–2047.

4. Balram C, Sabapathy K, Fei G, Khoo KS, Lee EJD. Genetic polymorphisms of UDP-glucuronosyltransferase in Asians: UGT1A1*28 is a common allele in Indians. Pharmacogenetics 2002;12: 81–83.

5. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc. Natl. Acad. Sci. U.S.A. 1998;5: 8170–8174.

6. Borlak J, Thum T, Landt O, Erb K, Hermann R. Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert´s syndrome) in healthy subjects. Hepatology 2000;32: 792–795.

7. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP, Chowdhury R. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N. Engl. J. Med. 1995;333: 1171–1175.

8. Bosma PJ. Inherited disorders of bilirubin metabolism. J. Hepatol. 2003;38: 107–117.

9. Cebecauerova D, Jirasek T, Budisova L, Mandys V, Volf V, Novotna Z, Subhanova I, Hrebicek M, Elleder M, Jirsa M. Dual hereditary jaundice: simultaneous occurrence of mutations causing Gilbert´s and Dubin-Johnson syndrome. Gastroenterology 2005;129: 315–320.

10. Crigler JF, Jr, Najjar VA. Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics 1952;10: 169–179.

11. Farago B, Melegh B. Gilbert szindróma. Orvosi Hetilap. 2008;149: 1277–1282.

12. Gilbert A, Lereboullet P. La Cholémie simple familiale. Sem. Méd. 1901;21: 241–245.

13. Hawes EM. N-glucuronidation, a common pathway in human metabolism of drugs with a tertiary amine group. Drug Metab. Dispos. 1998;26: 830–837.

14. Jirsa M, Petrasek J, Vitek L. Linkage between A(TA)7TAA and -3279T>G mutations in UGT1A1 is not essential for pathogenesis of Gilbert syndrome. Liver Int. 2006;10: 1302–1303.

15. Kabícek P, Barnincová L. Juvenile hyperbilirubinaemia and its early manifestation in adolescence. Čas. Lék. čes. 2007;146: 528–532.

16. Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyl transferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum. Mutat. 2000;16: 297–306.

17. Kadakol A, Sappal BS, Ghosh SS, Lowenheim M, Chowdhury A, Chowdhury S, Santra A, Arias IM, Chowdhury JR, Chowdhury NR. Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. J. Med. Genet. 2001;38: 244–249.

18. Kaplan M, Hammerman C, Renbaum P, Klein G, Levy-Lahad E. Gilbert´s syndrome and hyperbilirubinaemia in AB0-incompatible neonates. Lancet 2000;356: 652–653.

19. Koiwai O, Aono S, Adachi Y, Kamisako T, Yasui Y, Nishizawa M, Sato H. Crigler-Najjar syndrome type II is inherited both as a dominant and as a recessive trait. Hum. Mol. Genet. 1996;5: 645–647.

20. Maruo Y, D´Addario C, Mori A, Iwai M, Takahashi H, Sato H, Takeuchi Y. Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of UGT1A1 as the principal cause of Gilbert syndrome. Hum. Genet. 2004;115: 525–526.

21. Maruo Y, Serdaroglu E, Iwai M, Takahashi H, Mori A, Bak M, Calkavur S, Sato H, Takeuchi Y. A novel missense mutation of the bilirubin UDP-glucuronosyltransferase gene in a Turkish patient with Crigler-Najjar syndrome type I. J. Pediatr. Gastroenterol. Nutr. 2003;37: 627–630.

22. Monaghan G, McLellan A, McGeehan A, Li Volti S, Mollica F, Salemi I, Din Z, Cassidy A, Hume R, Burchell B. Gilbert’s syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn. J. Pediatr. 1999;134: 441–446.

23. Muchová L, Kráslová I, Lenícek M, Vítek L. Gilbert’s syndrome – myths and reality. Čas. Lék. čes. 2004;143: 375–380.

24. Peters WHM, Morsche RHM, Roelofs HMJ. Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications for patients with Gilbert´s syndrome. J. Hepat. 2003;38: 3–8.

25. Servedio V, d´Apolito M, Maiorano N, Minuti B, Torricelli F, Ronchi F, Zancan L, Perrotta S, Vajro P, Boschetto L, Iolascon A. Spectrum of UGT1A1 mutations in Crigler-Najjar (CN) syndrome patients: Identification of twelve novel alleles and genotype-phenotype correlation. Hum. Mutat. 2005;25: 325–333.

26, Strassburg CP, Manns MP. Jaundice, genes and promoters. J. Hepat. 2000;33: 476–479.

27. Strassburg CP. Pharmacogenetics of Gilbert’s syndrome. Pharmacogenomics 2008;9: 703–715.

28. Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, Owens IS, Negishi M, Sueyoshi T. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 2001;33: 1232–1238.

29. Sugatani J, Yamakawa K, Yoshinari K, Machida T, Takagi H, Mori M, Kakizaki S, Sueyoshi T, Negishi M, Miwa M. Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia. Biochem. Biophys. Res. Commun. 2002;292: 492–497.

30. Šašinka M. Choroby pečene. In: Šašinka M, Šagát T, Kovács L. Pediatria. Bratislava: Herba, 2007: 417–446.

31. Tukey RH, Strassburg CP. Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract. Mol. Pharmacol. 2001;59: 405–414.

32. von Ahsen N, Oellerich M, Schütz E. DNA base bulge vs unmatched end formation in probe-based diagnostic insertion/deletion genotyping: genotyping the UGT1A1 (TA)(n) polymorphism by real-time fluorescence PCR. Clin. Chem. 2000;46: 1939–1945.

33. Zmetáková I, Ferák V, Minárik G, Ficek A, Poláková H, Feráková E, Kádasi L. Identification of the deletions in the UGT1A1 gene of the patients with Crigler-Najjar syndrome type I from Slovakia. Gen. Physiol. Biophys. 2007;26: 306–310.

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