Gilbert's Syndrome - Cause

Cause

Gilbert's syndrome is a phenotypic effect, characterized by mild jaundice due to increased unconjugated bilirubin, that arises from several different genotypic variants of the gene for the enzyme responsible for changing bilirubin to the conjugated form.

Gilbert's syndrome is characterized by a 70–80% reduction, rather than more severe loss of activity, in the glucuronidation activity of the enzyme, uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UDP-glucuronosyltransferase 1A1, or UGT1A1). The UGT1A1 gene is located on human chromosome 2.

There are considerably in excess of 100 variants of the UGT1A1 gene, designated as UGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of its promoter region. The UGT1A1 gene is associated with a TATA box promoter region ; this region most commonly contains the genetic sequence A(TA₆)TAA; this variant accounts for about 50% of alleles in many populations. There are however several allelic polymorphic variants of this region, the most common adding another dinucleotide repeat TA to the promoter region, so that it is thus referred to as A(TA₇)TAA, being also called UGT1A1*28; this common variant accounts for about 40% of alleles in some populations, but is seen less often, approximately 3% of alleles, in southeast and east Asian people and Pacific Islanders.

In most populations, Gilbert's syndrome is most commonly associated with homozygous A(TA₇)TAA alleles. In 94% of GS cases, two other glucuronosyltransferase enzymes, UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective), are also affected.

However, Gilbert's syndrome can arise without TATA box promoter polymorphic mutations; in some populations, particularly healthy southeast and east Asians, Gilbert's syndrome is more often a consequence of heterozygote missense mutations (such as Gly71Arg also known as UGT1A1*6, Tyr486Asp also known as UGT1A1*7, Pro364Leu also known as UGT1A1*73) in the actual gene coding region, which may be associated with significantly higher bilirubin levels.

Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as a minor inborn error of metabolism.