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Drug Metab Dispos. 2018 Nov 1. pii: dmd.118.084368. doi: 10.1124/dmd.118.084368. [Epub ahead of print]

A Novel Pathogenic UGT1A1 Variant in a Sudanese Child with Type I Crigler-Najjar Syndrome.

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Milton S. Hershey Penn State Medical Center.
University of Helsinki.
Yale University School of Medicine.
Columbia University Medical Center.
University of Florida School of Medicine.
University of Helsinki;
Yale University School of Medicine;


Uridine diphosphate glucuronosyltransferases (UGTs) are key enzymes responsible for the body's ability to process of a variety of endogenous and exogenous compounds. Significant gains in the understanding of UGT function have come from the analysis of variants seen in patients. We cared for a Sudanese child who presented with clinical features of Type I Crigler-Najjar syndrome (CN-I), namely severe unconjugated hyperbilirubinemia leading to liver transplantation. CN-I is an autosomal recessive disorder caused by damaging mutations in the gene for UGT1A1, the hepatic enzyme responsible for bilirubin conjugation in humans. Clinical genetic testing was unable to identify a known pathogenic UGT1A1 mutation in this child. Instead, a novel homozygous variant resulting in an in-frame deletion, Val275del, was noted. Sanger sequencing demonstrated that this variant segregated with the disease phenotype in this family. We further performed functional testing using recombinantly expressed UGT1A1 with and without the patient variant, demonstrating that Val275del results in a complete lack of glucuronidation activity, a hallmark of CN-I. Sequence analysis of this region shows a high degree of conservation across all known catalytically active human UGTs, further suggesting that it plays a key role in the enzymatic function of UGTs. Finally, we note that the patient's ethnicity likely played a role in his variant being previously undescribed, and advocate for greater diversity and inclusion in genomic medicine.


bile acid metabolism/transport; enzyme mechanism; glucuronidation/UDP-glucuronyltransferases/UGT; liver disease


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