Crigler-Najjar syndrome type II in a Chinese boy resulting from three mutations in the bilirubin uridine 5′-diphosphate-glucuronosyltransferase (UGT1A1) gene and a family genetic analysis

Zheng, Bixia; Hu, Guorui; Yu, Jin; Liu, Zhifeng

doi:10.1186/1471-2431-14-267

Cited by 16 publications

(9 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our described patient has four different molecular variants. This is the first reported case of four variants in one patient; previous reports have identified three variants in a single patient [ 17 – 19 ]. It is not clear how multiple variants in the UGT1A1 gene affect the clinical status.…”

Section: Discussionmentioning

confidence: 70%

Case report: multiple UGT1A1 gene variants in a patient with Crigler-Najjar syndrome

et al. 2018

View full text Add to dashboard Cite

BackgroundInherited unconjugated hyperbilirubinemia is caused by variants in the gene UGT1A1 leading to Gilbert’s syndrome and Crigler-Najjar syndrome types I and II. These syndromes are differentiated on the basis of UGT1A1 residual enzymatic activity and its affected bilirubin levels and responsiveness to phenobarbital treatment.Case presentationIn this report, we present a boy with Crigler-Najjar syndrome type II with high unconjugated bilirubin levels that decreased after phenobarbital treatment but increased in adolescence. Four different UGT1A1 gene variants have been identified for this patient, of which one is novel (g.11895_11898del) most likely confirming diagnose molecularly.ConclusionsThe presented case highlights the challenges encountered with the interpretation of molecular data upon identification of multiple variants in one gene that are causing different degree reducing effect on enzyme activity leading to several clinical conditions.

show abstract

Section: Discussionmentioning

confidence: 70%

Case report: multiple UGT1A1 gene variants in a patient with Crigler-Najjar syndrome

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Additionally, UGTs can metabolize some endogenous substances. For example, UGT1A1 is the major enzyme involved in the metabolic elimination of bilirubin (Zheng et al, 2014). UGT1A3 can conjugate the bile acids (Erichsen et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

New insights into the risk of phthalates: Inhibition of UDP-glucuronosyltransferases

et al. 2016

View full text Add to dashboard Cite

Wide utilization of phthalates-containing products results in the significant exposure of humans to these compounds. Many adverse effects of phthalates have been documented in rodent models, but their effects in humans exposed to these chemicals remain unclear until more mechanistic studies on phthalate toxicities can be carried out. To provide new insights to predict the potential adverse effects of phthalates in humans, the recent study investigated the inhibition of representative phthalates di-n-octyl ortho-phthalate (DNOP) and diphenyl phthalate (DPhP) towards the important xenobiotic and endobiotic-metabolizing UDP-glucuronosyltransferases (UGTs). An in vitro UGTs incubation system was employed to study the inhibition of DNOP and DPhP towards UGT isoforms. DPhP and DNOP weakly inhibited the activities of UGT1A1, UGT1A7, and UGT1A8. 100 µM of DNOP inhibited the activities of UGT1A3, UGT1A9, and UGT2B7 by 41.8% (p < 0.01), 45.6% (p < 0.01), and 48.8% (p < 0.01), respectively. 100 µM of DPhP inhibited the activity of UGT1A3, UGT1A6, and UGT1A9 by 81.8 (p < 0.001), 49.1% (p < 0.05), and 76.4% (p < 0.001), respectively. In silico analysis was used to explain the stronger inhibition of DPhP than DNOP towards UGT1A3 activity. Kinetics studies were carried our to determine mechanism of inhibition of UGT1A3 by DPhP. Both Dixon and Lineweaver-Burk plots showed the competitive inhibition of DPhP towards UGT1A3. The inhibition kinetic parameter (Ki) was calculated to be 0.89 µM. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1>[I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), these studies predicted in vivo drug-drug interaction might occur when the plasma concentration of DPhP was above 0.089 µM. Taken together, this study reveales the potential for adverse effects of phthalates DNOP and DPhP as a result of UGT inhibition.

show abstract

“…Variants c.211G>A (p.G71R) and c.1456T>G (p.Y486D) are the most frequently reported mutation sites in Asian CNS2 patients. [24][25][26] In our patients, UGT1A1 sequencing analysis was performed. Patient 1 is a compound heterozygote with mutations c.-3279T>G, G71R, and S191F.…”

Section: Discussionmentioning

confidence: 99%

UGT1A1-related Bilirubin Encephalopathy/Kernicterus in Adults

Bai¹,

Lu²,

Liu³

et al. 2021

Journal of Clinical and Translational Hepatology

View full text Add to dashboard Cite

Background and Aims: Bilirubin encephalopathy/kernicterus is very rare in adults. This study is aimed to investigate the clinical manifestations and genetic features of two patients with UGT1A1-related kernicterus. Methods: Sanger sequencing analysis was performed to identify UGT1A1 gene mutations in the patients and their families. Bioinformatics analysis was used to predict the potential functional effects of novel missense mutations. Clinical manifestations and biochemical parameters were collected and analyzed. Results: Two patients with Crigler-Najjar syndrome type II (CNS2) developed kernicterus in adulthood. Sanger sequencing identified a compound heterozygous mutation in the UGT1A1 gene in patient 1, which was inherited from his mother (G71R) and his father (c.-3279T>G; S191F). Patient 2 carried three heterozygous mutations, namely G71R, R209W and M391K; among which, the M391K mutation has not been reported before. Multiple prediction software showed that the M391K mutation was pathogenic. Symptoms were relieved in the two patients after phenobarbital and artificial liver support treatment. Patient 1 also underwent liver transplantation. Conclusions: Adults with CNS2 are at risk for kernicterus. Phenobarbital treatment is beneficial for maintaining bilirubin levels and preventing kernicterus.

show abstract

Crigler-Najjar syndrome type II in a Chinese boy resulting from three mutations in the bilirubin uridine 5′-diphosphate-glucuronosyltransferase (UGT1A1) gene and a family genetic analysis

Cited by 16 publications

References 15 publications

Case report: multiple UGT1A1 gene variants in a patient with Crigler-Najjar syndrome

Case report: multiple UGT1A1 gene variants in a patient with Crigler-Najjar syndrome

New insights into the risk of phthalates: Inhibition of UDP-glucuronosyltransferases

UGT1A1-related Bilirubin Encephalopathy/Kernicterus in Adults

Contact Info

Product

Resources

About