A novel pathogenic UGT1A1 variant in a Sudanese child with type 1 crigler-najjar syndrome

Walaa Elfar, Erkka Järvinen, J. I. Weizhen, Johanna Mosorin, Annalisa G. Sega, Alina C. Iuga, Steven J. Lobritto, Monica Konstantino, Albert Chan, Moshe Finel, Saquib A. Lakhani

Research output: Contribution to journalArticle

Abstract

Uridine diphosphate glucuronosyltransferases (UGTs) are key enzymes responsible for the body’s ability to process a variety of endogenous and exogenous compounds. Significant gains in understanding UGT function have come from the analysis of variants seen in patients. We cared for a Sudanese child who showed clinical features of type 1 Crigler-Najjar syndrome (CN-1), namely severe unconjugated hyperbilirubinemia leading to liver transplantation. CN-1 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, p.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 p.Val275del results in a complete lack of glucuronidation activity, a hallmark of CN-1. 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.

Original languageEnglish (US)
Pages (from-to)45-48
Number of pages4
JournalDrug Metabolism and Disposition
Volume47
Issue number1
DOIs
StatePublished - Jan 2019

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Crigler-Najjar Syndrome
Glucuronosyltransferase
Uridine Diphosphate
Mutation
Aptitude
Hyperbilirubinemia
Genetic Testing
Bilirubin
Liver Transplantation
Sequence Analysis
Medicine
Phenotype
Liver
Enzymes
Genes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Elfar, W., Järvinen, E., Weizhen, J. I., Mosorin, J., Sega, A. G., Iuga, A. C., ... Lakhani, S. A. (2019). A novel pathogenic UGT1A1 variant in a Sudanese child with type 1 crigler-najjar syndrome. Drug Metabolism and Disposition, 47(1), 45-48. https://doi.org/10.1124/dmd.118.084368
Elfar, Walaa ; Järvinen, Erkka ; Weizhen, J. I. ; Mosorin, Johanna ; Sega, Annalisa G. ; Iuga, Alina C. ; Lobritto, Steven J. ; Konstantino, Monica ; Chan, Albert ; Finel, Moshe ; Lakhani, Saquib A. / A novel pathogenic UGT1A1 variant in a Sudanese child with type 1 crigler-najjar syndrome. In: Drug Metabolism and Disposition. 2019 ; Vol. 47, No. 1. pp. 45-48.
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Elfar, W, Järvinen, E, Weizhen, JI, Mosorin, J, Sega, AG, Iuga, AC, Lobritto, SJ, Konstantino, M, Chan, A, Finel, M & Lakhani, SA 2019, 'A novel pathogenic UGT1A1 variant in a Sudanese child with type 1 crigler-najjar syndrome', Drug Metabolism and Disposition, vol. 47, no. 1, pp. 45-48. https://doi.org/10.1124/dmd.118.084368

A novel pathogenic UGT1A1 variant in a Sudanese child with type 1 crigler-najjar syndrome. / Elfar, Walaa; Järvinen, Erkka; Weizhen, J. I.; Mosorin, Johanna; Sega, Annalisa G.; Iuga, Alina C.; Lobritto, Steven J.; Konstantino, Monica; Chan, Albert; Finel, Moshe; Lakhani, Saquib A.

In: Drug Metabolism and Disposition, Vol. 47, No. 1, 01.2019, p. 45-48.

Research output: Contribution to journalArticle

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T1 - A novel pathogenic UGT1A1 variant in a Sudanese child with type 1 crigler-najjar syndrome

AU - Elfar, Walaa

AU - Järvinen, Erkka

AU - Weizhen, J. I.

AU - Mosorin, Johanna

AU - Sega, Annalisa G.

AU - Iuga, Alina C.

AU - Lobritto, Steven J.

AU - Konstantino, Monica

AU - Chan, Albert

AU - Finel, Moshe

AU - Lakhani, Saquib A.

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N2 - Uridine diphosphate glucuronosyltransferases (UGTs) are key enzymes responsible for the body’s ability to process a variety of endogenous and exogenous compounds. Significant gains in understanding UGT function have come from the analysis of variants seen in patients. We cared for a Sudanese child who showed clinical features of type 1 Crigler-Najjar syndrome (CN-1), namely severe unconjugated hyperbilirubinemia leading to liver transplantation. CN-1 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, p.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 p.Val275del results in a complete lack of glucuronidation activity, a hallmark of CN-1. 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.

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