2.1. Crigler-Najjar Syndrome

At least 85 mutations in the UGT1A1 gene that cause Crigler-Najjar syndrome have been identified. This condition occurs when both copies of the UGT1A1 gene in each cell are altered. Crigler-Najjar syndrome is characterized by high levels of unconjugated bilirubin in the blood (unconjugated hyperbilirubinemia) and yellowing of the skin and eyes (jaundice). Some affected individuals develop a form of brain damage called kernicterus due to the accumulation of unconjugated bilirubin in the brain, which can be lethal.

Mutations in the UGT1A1 gene that cause Crigler-Najjar syndrome result in reduced or absent function of the bilirubin-UGT enzyme. People with Crigler-Najjar syndrome type 1 (CN1) have no enzyme function, while people with Crigler-Najjar syndrome type 2 (CN2) have less than 20 percent of normal function. The signs and symptoms of CN1 are more severe than those of CN2. The loss of bilirubin-UGT function decreases glucuronidation of unconjugated bilirubin. This toxic substance then builds up in the body, causing hyperbilirubinemia, jaundice, and sometimes, kernicterus.

2.2. Gilbert Syndrome

Changes in the UGT1A1 gene can cause Gilbert syndrome. This condition is characterized by periods of mild unconjugated hyperbilirubinemia, which rarely leads to episodes of jaundice.

Gilbert syndrome occurs worldwide, but some mutations are seen more often in particular populations. In many populations, the most common genetic change that causes Gilbert syndrome occurs in an area near the UGT1A1 gene called the promoter region, which controls the production of the bilirubin-UGT enzyme. This change must occur in both copies of the UGT1A1 gene to cause Gilbert syndrome. The common genetic change involved in Gilbert syndrome, called UGT1A1*28, results from the addition of two DNA building blocks (nucleotides) to an important sequence in the promoter region known as the TATA box. The normal UGT1A1 TATA box sequence is written as A(TA)₆TAA. The UGT1A1*28 sequence includes an extra TA nucleotide pair and is written as A(TA)₇TAA. This genetic change creates a longer than normal TATA box and impairs protein production.

The UGT1A1*28 change, however, is uncommon in Asian populations. Asians with Gilbert syndrome often have a mutation in one copy of the UGT1A1 gene that results in the change of a single protein building block (amino acid) in the bilirubin-UGT enzyme. The most common mutation in this population replaces the amino acid glycine with the amino acid arginine at position 71 of the enzyme (written as Gly71Arg or G71R). This type of mutation, known as a missense mutation, results in reduced enzyme function.

People with Gilbert syndrome have approximately 30 percent of normal bilirubin-UGT enzyme function. As a result, unconjugated bilirubin is not glucuronidated quickly enough, and it builds up in the body, causing mild hyperbilirubinemia.

2.3. Warfarin Resistance

2.4. Other Disorders

Although jaundice is common in newborns, mutations in the UGT1A1 gene increase the risk of developing a more severe condition called transient familial neonatal hyperbilirubinemia. In this condition, severe unconjugated hyperbilirubinemia and jaundice occur in newborns and usually disappear in 1 to 2 weeks. Some babies develop kernicterus (which can be lethal), hearing loss, or other neurological problems. The G71R mutation is the most common mutation associated with transient familial neonatal hyperbilirubinemia. Asian but not white newborns with a UGT1A1 gene mutation seem to be at risk of developing this condition.

Sometimes newborn jaundice is associated with breastfeeding: Unconjugated bilirubin levels increase when the baby is breastfed, causing jaundice, and return to normal when breastfeeding is stopped for a prolonged period. This condition, often called breast milk jaundice, appears 5 or 10 days after birth and disappears at around 4 months of age. Kernicterus is not typically seen in infants with breast milk jaundice. Research suggests that a substance in the breast milk of mothers of affected infants blocks glucuronidation. In addition, many affected infants have a mutation in one copy of the UGT1A1 gene, most commonly the G71R mutation, and the mutation is thought to underlie the unconjugated hyperbilirubinemia. The substance in the breast milk may trigger the buildup of unconjugated bilirubin in infants with already impaired bilirubin-UGT enzyme function.