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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e318234ecd9
Case Reports

UGT1A1 Genotype in a White Boy With Crigler-Najjar Syndrome Type 2

Peña, Luis*; Pico, Miguel; Rosatelli, Cristina; Meloni, Antonella; del Río, Elisabeth§; Tizzano, Eduardo F.§; Baiget, Montserrat§

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*Hospital Universitario Materno-Infantil

Hospital Universitario de Gran Canaria Dr Negrin. Las Palmas de Gran Canaria, Spain

Dipartimento di Scienze Biomediche e Biotecnologie, Università degli Studi di Cagliari, Cagliari, Italy

§Hospital de la Santa Creu i Sant Pau, CIBERER, Barcelona U-705, Spain.

Address correspondence and reprint requests to Montserrat Baiget, Servei de Genètica, Hospital de la Santa Creu i Sant Pau, Sant Quintí 89, 08041 Barcelona, Spain (e-mail:

Received 19 July, 2011

Accepted 28 August, 2011

Drs Peña and Pico contributed equally to this work.

The authors report no conflicts of interest.

We report a white boy with Crigler-Najjar type 2 (CN-2) syndrome who was found to be homozygous for a rare A(TA)8TAA allele in the promoter region of the UGT1A1 gene and a T>G substitution at position −3279 in the gtPBREM (PhenoBarbitalResponsiveElementModule) predicted to respond to phenobarbital treatment. The 3 types of CN syndrome are caused by mutations in the UGT1A1 gene that results in reduction or lack of the enzymatic activity. The enzyme is completely absent in CN-1 patients, severely reduced in CN-2, and moderately to slightly reduced in patients with Gilbert syndrome (GS).

The identification of the UGT1A1 locus on chromosome 2 (2q37) that encodes for UGT1A1 has provided the tools for the molecular study of inherited hyperbilirubinemias (1) and references therein. The genetic defect in almost all of the cases of GS in whites is a thymine-adenine (TA) insertion in the regulatory TATA box of the UGT1A1 gene promoter. Affected individuals are homozygous for the variant promoter and have 7 TA repeats (A(TA)7TAA) instead of 6 TA repeats (A(TA)6TAA), which represents the normal situation. Promoters with 5 and 8 repeats have also been identified, primarily in individuals of African descent, and it has been demonstrated that the transcriptional activity of the UGT1A1 promoter decreases as the number of TA repeats increases from 5 to 8. In particular, the presence of the A(TA)7TAA allele determines a transcriptional reduction of >50%.

A distal enhancer sequence gtPBREM is located at −3499/−3210 upstream from the transcriptional start of the UGT1A1 gene. The gtPBREM sequence is 290-bp long and is regulated by a nuclear receptor known as constitutive androstane receptor (CAR) in response to phenobarbital treatment. A T-to-G substitution at nucleotide −3279 in the gtPBREM of the UGT1A1 gene reduces the transcriptional activity by 40% and is able to induce hyperbilirubinemia in homozygous status or in combination with the variant A(TA)7TAA. Phenobarbital is used as a therapeutic drug for patients with CN-2 syndrome because it increases the expression of bilirubin glucuronosyltransferase and reduces the incidence of unconjugated hyperbilirubinemia.

We report a white boy who was born full-term in Gran Canaria Island in 2003. He was severely icteric without hepatosplenomegaly, and a marked hyperbilirubinemia (250 μmol/L) was measured on his fourth day of life. At 11 days of life, he was admitted in the neonatal unit because of persistent jaundice with a level of unconjugated bilirubin of 440 μmol/L. After phototherapy treatment, this value decreased until 238 μmol/L and exclusive artificial feeding was initiated. At month 2, laboratory investigations revealed a consistent elevated unconjugated hyperbilirubinemia (275 μmol/L). The results of other liver function tests, glucose-6-phosphate dehydrogenase activity, and hematologic tests were normal. Immunologic tests for hepatitis A, B, and C were negative. Serum bilirubin was reduced to a level of 42 μmol/L after phenobarbital treatment (5 mg · kg−1 · day−1) during 12 weeks. This boy is now 6 years old, asymptomatic with normal height and weight and psychomotor development. He is still receiving intermittently oral phenobarbital. All of the members of the family were originally from Gran Canaria.

The analysis of the UGT1A1 gene and the gtPBREM region was performed as previously described (2). Results revealed that our patient was homozygous for the A(TA)7TAA allele, whereas the coding regions and exon-intron junctions were normal. The study of the gtPBREM showed the presence of −3279 T > G substitution in homozygous state. The parents were heterozygous carriers of both mutations, thus excluding the presence of a deletion in the 5′ region of the UGT1A1 gene.

To the best of our knowledge, this is the first description of a white patient with CN-2 who is homozygous for the rare A(TA)7TAA allele in the promoter region of the UGT1A1 gene and of the T > G substitution at position −3279 in the gtPBREM.

The A(TA)7TAA allele was first described in subjects of African ancestry with an allele frequency of 6.9%. TheTA8 allele is extremely rare in whites given that only a few cases have been described. The first was an Italian girl with genotype TA7/TA8 (3), followed by a Greek boy (4) with genotype TA6/TA8 and a Mexican mestizo (TA7/TA8) (5). The association of a homozygous TA8 promoter polymorphism and a missense mutation of UGT1A1 in a Moroccan girl with CN-2 has been reported (2). More recently, 2 Portuguese girls with genotype TA7/TA8 have been reported (6). In a study of healthy Slovenian population, a case with TA7/TA8 has been found (7), and in an extensive survey of Croatian subjects suspected of having GS, 3 subjects carrying a TA8 allele were found (8). Anonymous DNA samples of American residents with ancestry from all of the major regions of the world were studied and 9 individuals who carried a TA8 allele were identified. A study performed on Spanish neonates showed the already known association between neonatal jaundice and the presence of the A(TA)7TAA variant, which was the only allele associated with GS in this population (1). From these data, we can conclude that the A(TA)7TAA variant is extremely rare in the white population. This is probably a recent spontaneous mutation and is not derived from the chromosomes of African origin. The repeated sequences in the human genome are highly unstable and can lengthen or shorten by different mechanisms such as unequal crossing-over during meiosis or strands slippage during DNA replication. Indeed, the genetic background of the Canary Islands is characterized by an isolated population and high rates of consanguinity that may explain the unique genotype of our patient.

The principal cause of GS in whites is a synergistic reduction of transcriptional activity caused by the linked mutations A(TA)7TAA and −3279 T > G. The gtPBREM DR3 mutation is associated with similar reduced transcriptional activity despite the presence or absence of the nuclear receptor CAR. However, the −3279 T > G mutation may not affect the activation of the gtPBREM by CAR. It is likely that CAR regulates the gtPBREM by binding to gtNR1 in response to phenobarbital induction, whereas the DR3 may be regulated by other yet unidentified factors. Thus, individuals carrying the −3279 T > G mutation may respond to phenobarbital treatment, which induces residual UGT1A1 activity, with consequent reduction of bilirubin concentrations. This was the case in our patient with CN-2 that showed a positive response to phenobarbital therapy.

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Copyright 2012 by ESPGHAN and NASPGHAN


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