Genetic defects at the UGT1 locus associated with Crigler-Najjar type I disease, including a prenatal diagnosis.
Characterization of the UGT1 gene complex locus encoding both multiple bilirubin and phenol UDP-glucuronosyltransferases (transferases) has been critical in identifying mutations in the bilirubin isoforms. This study utilizes this information to identify the bases of deficient bilirubin UDP-glucuronosyltransferase activity encoded by the UGT1A gene for the major bilirubin isozyme, HUG-Br1, in 3 Crigler-Najjar type I individuals and the genotype of an at-risk unborn sibling of one patient. A homozygous and heterozygous two-base mutation (CCC to CGT) created the HUG-Br1P387R mutant of the major bilirubin transferase in 2 different Crigler-Najjar type I patients, B.G. and G.D., respectively. Both parents of B.G. and his unborn sibling, J.G., were determined to be carriers of the P387R mutation. G.D. also contains the CAA to TAA nonsense mutation (G1n357st). Y.A. has a homozygous CT deletion in codons 40/41. The HUG-Br1P387R mutant protein was totally inactive at the major pH optimum (6.4), but retained 26% normal activity at the minor pH optimum (7.6), which was 5.4% of the combined activities measured at the two pH values.
Ciotti
M
M
Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
Obaray
R
R
Martín
M G
MG
Owens
I S
IS
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001663:Bilirubin / Q000737:chemistry; D015139:Blotting, Southern; D002675:Child, Preschool; D002845:Chromatography; D003001:Cloning, Molecular; D018389:Codon, Nonsense / Q000302:isolation & purification; D003414:Crigler-Najjar Syndrome / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D005878:Gilbert Disease / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015151:Immunoblotting; D007231:Infant, Newborn; D007536:Isomerism; D008297:Male; D009154:Mutation; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D011296:Prenatal Diagnosis / Q000379:methods; D017384:Sequence Deletion; D014162:Transfection
D018389:Codon, Nonsense; C019787:bilirubin glucuronoside glucuronosyltransferase; D004247:DNA; D014453:Glucuronosyltransferase; D001663:Bilirubin