Co-occurrence of three different mutations in the bilirubin UDP-glucuronosyltransferase gene in a Chinese family with Crigler-Najjar syndrome type I and Gilbert's syndrome.
Crigler-Najjar syndrome type I is a severe form of hereditary unconjugated hyperbilirubinemia and is caused by homozygous or compound heterozygous mutations of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1). We analyzed the bilirubin UDP-glucuronosyltransferase gene in a female Chinese patient with Crigler-Najjar syndrome type I. Relatives of the patient were also analyzed. The patient was homozygous for a nonsense mutation of R341X. The patient's father, sister and brother, all diagnosed with Gilbert's syndrome, were compound heterozygotes of R341X, P229Q, and an insertion mutation of the TATA box [A(TA)7TAA]. Heterozygotes of nonsense mutations (Q331X and C280X) in our previous study had either Crigler-Najjar syndrome type II or Gilbert's syndrome, but heterozygotes of R341X (mother and grandmothers) were normal. An in vitro expression study of homozygous and heterozygous models of R341X showed 0 and 58%, respectively, of normal enzyme activity. Therefore, the present results indicate that carriers of the nonsense mutation could be normal for plasma bilirubin concentration, Gilbert's syndrome and Crigler-Najjar syndrome type II. The results also suggest the importance of the accumulation of prevalent or polymorphic mutation in the etiology of Gilbert's syndrome and Crigler-Najjar syndrome type II.
Maruo
Y
Y
Department of Pediatrics, Shiga University of Medical Science, Seta, Otsu, Japan. maruo@belle.shiga-med.ac.jp
Poon
K K-H
KK
Ito
M
M
Iwai
M
M
Takahashi
H
H
Mori
A
A
Sato
H
H
Takeuchi
Y
Y
D000328:Adult; D019943:Amino Acid Substitution; D001483:Base Sequence; D002675:Child, Preschool; D002681:China / Q000208:ethnology; D018389:Codon, Nonsense; D003241:Consanguinity; D003414:Crigler-Najjar Syndrome / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005878:Gilbert Disease / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree
D018389:Codon, Nonsense; C019787:bilirubin glucuronoside glucuronosyltransferase; D014453:Glucuronosyltransferase