Crigler-Najjar syndrome type 1

Crigler-Najjar syndrome type I (CN-I) is a rare and severe metabolic disorder due to mutations in the gene UGT1A1.

Uridine-diphosphoglucuronate glucuronosyltransferases (UGTs) are a family of enzymes that conjugate various endogenous and exogenous compounds with glucuronic acid and facilitate their excretion in the bile.

Bilirubin-UGT(1) (UGT1A1) is the only isoform that significantly contributes to the conjugation of bilirubin.

Lesions in the gene encoding bilirubin-UGT(1), lead to complete or partial inactivation of the enzyme causing the rare autosomal recessively inherited conditions, Crigler-Najjar syndrome type-1 (CN-1) and type 2 (CN-2), respectively.

Inactivation of the enzyme leads to accumulation of unconjugated bilirubin in the serum.

Severe hyperbilirubinemia seen in CN-1 can cause bilirubin encephalopathy (kernicterus). Kernicterus can be fatal or may leave behind permanent neurological sequelae.

See also: Gilbert syndrome

In contrast to Crigler-Najjar syndromes, Gilbert syndrome is a common inherited condition characterized by mild hyperbilirubinemia.

An insertional mutation of the TATAA element upstream to UGT1A1 results in a reduced level of expression of the gene.

Homozygosity for the variant promoter is required for Gilbert syndrome, but not sufficient for manifestation of hyperbilirubinemia, which is partly dependent on the rate of bilirubin production.

Several structural mutations of UGT1A1, for example, a G71R substitution, have been reported to cause mild reduction of UGT activity toward bilirubin, resulting in mild hyperbilirubinemia, consistent with Gilbert syndrome.

When the normal allele of a heterozygote carrier for a Crigler-Najjar type structural mutation contains a Gilbert type promoter, intermediate levels of hyperbilirubinemia, consistent with the diagnosis of CN-2, may be observed.

Mutations

 UGT1A1 c.1070A>G

• A recurrent mutation - c.1070A>G in exon 3 - was identified in the Tunisian population, suggesting a founder effect. In 2004, the detection of this mutation in two Kuwaiti Bedouin families has called the Tunisian founder effect in question again.
• Haplotype analysis confirmed the founder effect hypothesis and dated the appearance of this mutation some 32 generations ago in the Tunisian population.
• The blending of the Bedouin nomads within today’s Tunisian population. After population migration from east to west, this mutation was introduced into the Tunisian population, and then perpetuated, probably because of marriages in isolated communities.