Correspondence

The Genetic Basis of Gilbert's Syndrome

N Engl J Med 1996; 334:802-803March 21, 1996

Article

To the Editor:

In the study by Bosma et al. (Nov. 2 issue)1 of the genetic basis of Gilbert's syndrome, the relevance of the variant TATAA element is far from certain. The authors do not provide data or cite references that demonstrate that a quantitative reduction in bilirubin UDP-glucuronosyltransferase 1 (bilirubin/uridine diphosphoglucuronate-glucuronosyltransferase 1) in patients with Gilbert's syndrome is related to transcriptional rather than translational or post-translational mechanisms. Furthermore, the normal functional characteristics of the native promoter are not made clear. Is transcription regulated by constitutive or inducible mechanisms? this point is relevant because the experiments were restricted to four steady-state transfections into a single liver cell line. Under stimulated conditions, is the function of the variant promoter still defective? Were the experiments repeated in other relevant cell lines?

Paul Mathew, M.D.
10201 Gateway West, El Paso, TX 79925

1 References

1. 1

   Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995;333:1171-1175
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We did not present data showing that the reduced activity of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome is accompanied by reduced levels of messenger RNA (mRNA) and protein. The demonstration of this would require liver samples from patients and controls. Our results are based on genetic data and in vitro studies.

We showed that the sequence of the bilirubin UDP-glucuronosyltransferase 1 coding region and the 5' untranslated region is normal in patients with Gilbert's syndrome. Thus, the ribosome entry site, the protein sequence, and all potential glycosylation sites are identical to those in controls. Since the mRNA is identical in both groups, a reduction in the activity or level of bilirubin UDP-glucuronosyltransferase 1 can be explained by a decrease in mRNA levels, a difference in translation, or post-translational modification. A difference in translation or post-translational modification of identical mRNAs implies that a factor involved in these processes is affected. If this were the case the expression of additional proteins would be affected. Since in Gilbert's syndrome only bilirubin UDP-glucuronosyltransferase 1 activity is reduced, an effect on translation or on post-translational processing is unlikely to be the cause.

A decreased level of mRNA, resulting in reduced protein levels, can be explained by a decrease in transcription or stability. Our data do not exclude the presence of a second mutation, in an intron or 3' untranslated region, that affects the stability of bilirubin UDP-glucuronosyltransferase 1 mRNA. This mutation, however, would be present on the allele containing the longer TATAA box. If reduced bilirubin glucuronidation is not linked to the longer TATAA box, the presence of the box in patients with Gilbert's syndrome would be a matter of chance. The frequency of the long-TATAA-box allele in the general population is 40 percent; thus, the likelihood of being homozygous for this abnormal allele is 0.4² (16 percent), and the likelihood that 10 unrelated patients with Gilbert's syndrome will be homozygous is 0.4²⁰ (1 in 10⁸). Even if another mutation does exist, it should be linked to the abnormal TATAA box, making this box a reliable genetic marker for Gilbert's syndrome.

Our functional studies showed that the TATAA-box abnormality resulted in the reduced expression of a reporter gene. This reduced expression can explain the decreased bilirubin UDP-glucuronosyltransferase 1 activity in patients with Gilbert's syndrome. Bilirubin glucuronidation can be induced in such patients.1 An effect of the longer TATAA box on the constitutive expression of this enzyme is therefore likely; however, a possible effect of this box on induction should be investigated.

Piter J. Bosma, Ph.D.
Academic Medical Center, 1105 AZ Amsterdam, the Netherlands

Ben A. Oostra, Ph.D.
Erasmus University, 3015 GE Rotterdam, the Netherlands

1 References

1. 1

   Black M, Sherlock S. Treatment of Gilbert's syndrome with phenobarbitone. Lancet 1970;1:1359-1361
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Ernest Beutler, Terri Gelbart, William Miller. (2002) Severe Jaundice in a Patient with a Previously Undescribed Glucose-6-phosphate Dehydrogenase (G6PD) Mutation and Gilbert Syndrome. Blood Cells, Molecules, and Diseases 28:2, 104-107
   CrossRef

2. 2

   Stratton, John F., Gayther, Simon A., Russell, Paul, Dearden, Jo, Gore, Martin, Blake, Peter, Easton, Doug, Ponder, Bruce A.J., . (1997) Contribution of BRCA1 Mutations to Ovarian Cancer. New England Journal of Medicine 336:16, 1125-1130
   Full Text