Barbot, José

Costa, Elísio

Santos, Rosário

Santos-Silva, Ermelinda

Vieira, Emília

Haematologica

Biblioteca Digital do IPB

new policy of the journal research current issue back issues 1996 .. 1997 998'" 999 e-images sup:Jiernents f11i3il instru~:~tions submission peer-review search journats sites rnedline Haematologica 2002; 87:(04)ELT21 (fViE<i!ine] [prev] [index] [next] TATA-Box polymorphism in the uridine diphosphate glucuronosyl transferase gene in Portuguese patients with clinical diagnosis of Gilbert Syndrome Elisio Costa, 1 Emflia Vieira, 2 Ermelinda Santos-Silva,3 Jose Barbot, 1 Rosario dos Santos2 1 Servi~o de Hematologia. Hospital de Crian~as Maria Pia. Porta; 2Unidade de Genetica Molecular do Institute de Genetica Medica Doutor Jacinto de Magalhaes. Porto; 3Servic;o de Pediatria. Hospital de Crianc;as Maria Pia. Porta, Portugal. Correspondence: Elisio Costa, Servic;o de Hematologia , Hospital de Crianc;as Maria Pia, Rua da Boavista, 827, 4050-111 Porta, Portugal. E-mail: hematologia@hmariapia. min-saude. pt ----~~~-~· --------------------~ Gilbert Syndrome (GS) is an inherited form of mild unconjugated hyperbilirubinemia characterized by decreased bilirubin UDP-glucuronosyl transferase (UGT1A1) activity. GS is the most common alteration of the hepatic bilirubin metabolism, occurring in 2-12% of the population .1-5 A nonsense mutation of the UGT1A1 gene was identified in a patient with Crigler-Najjar Syndrome in 1992, but it was only in 1995 that mutations in UGT1A1 that caused GS were discovered. The most common genetic variant of the UGT1A1 gene is a TA insertion in the repetitive TATA-Box of the gene promoter, which normally consists of six repeats. 2 The TA(?) allele causes reduced expression of the gene, and homozygosity of this allele is typically associated with a mild form of GS1. The aim of our study was to determine the frequency of UGT1A1 gene variants in Portuguese patients with clinical diagnosis of GS. We screened 25 Portuguese patients with clinical diagnosis of GS: 6 females, ages 4-30 years, and 19 males, ages 1-35 years. The diagnosis of GS was based on the standard criteria6. The mean ( +/- SD) total bilirubin concentration was 45,15 +/- 25,18 mmoi/L. Genomic DNA was extracted from peripheral blood leukocytes using standard methods. Screening of the variants in the promoter of the UGT1Al gene was performed by polymerase chain reaction with primers described by Bancroft et al.? Analysis of the amplified DNA fragments was performed by automated capillary electrophoresis. Analysis of UGT1A1 promoter variants (Figure 1) revealed that 22 (88%) of the GS patients were homozygous for the mutant allele (TA(7)/TA(7)), and 3 (12%) were heterozygotes (TA(6)/ TA(?)). The high frequency of SG patients presenting this mutation is similar to that found in other popu!ations, namely in the Italian population where the homozygote frequency was seen to be 80%. 3 Based on the frequency observed in Caucasians, in several studies of small series, Beutler et al. 5 calculated a homozygote frequency of 15%. This predicted value is higher than that of patients with a clinical diagnosis of GS, which probably reflects the existence of other inherited or acquired factors affecting bilirubin metabolism, in addition to reduced alucuronidation caused bv the TA insertion. 2 Male element had a more significant elevation in serum bilirubin than the females. This is possibly due to the greater bilirubin load per kilogram of body weight in males or the inhibition of enzymatic glucuronidation by androgenic steroids, or both. 2 The higher levels may explain the sample bias of 19:6 (men/women) in our group of GS patients. In conclusion, our results suggest that the insertion of the TA dinuclotide in the promoter region of the gene of the UGT1A1 is the main cause of GS in the Portuguese population. References 1. Biondi ML, Turri 0, Dilillo D, Stival G, Guagnellini E. Contribution of the TATA-box genotype (Gilbert syndrome) to serum bilirubin concentrations in Italian population. Clinical Chemistry 1999;45:897-898. 2. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, Boer A, Oostra BA, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert syndrome. N Eng J Med 1995;333:1171-1175. 3. Pirulli D, Giordano M, Puzzer D, Crovella S, Rigato I, Tiribelli C, et al. Rapid method for detection of extra (TA) in the promoter of the bilirubin-UDP-glucuronosyl transferase 1 gene associated with Gilbert Syndrome. Clinical Chemistry 2000;46: 129-131. 4. Borlak j, Thum T, Landt 0, Erb K, Hermann R. Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert Syndrome) in healthy subjects. Hepatology 2000;32: 792-795. 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 USA 1998;95:8170-8174. 6. GentileS, Orzes N, Persico M, Marmo R, Bronzino P, Tiribelli C. Comparision of nicotinic acid and caloric restriction &endash;induced hyperbilirubinaemia in the diagnosis of Gilbert's syndrome. J Hepatol1985;1:537-543. 7. Bancroft JD, Kreamer B, Gourley GR. Gilbert syndrome accelerates development of neonatal jaundice. J Pediatr 1998; 132:656-660. © Copyrigllt 2oo·1. Allr·rghts reserved. ..... top 

TATA-box polymorphism in the urine diphosphate glucuronosyl transferase gene in Portuguese patients with clinical diagnosis of gilbert syndrome

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TATA-box polymorphism in the urine diphosphate glucuronosyl transferase gene in Portuguese patients with clinical diagnosis of gilbert syndrome

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