A mutation which disrupts the hydrophobic core of the signal peptide of bilirubin UDP-glucuronosyltransferase, an endoplasmic reticulum membrane protein, causes Crigler-Najjar type II.
Crigler-Najjar (CN) disease is caused by a deficiency of the hepatic enzyme, bilirubin UDP-glucuronosyltransferase (B-UGT). We have found two CN type II patients, who were homozygous for a leucine to arginine transition at position 15 of B-UGT1. This mutation is expected to disrupt the hydrophobic core of the signal peptide of B-UGT1. Wild type and mutant B-UGT cDNAs were transfected in COS cells. Mutant and wild type mRNA were formed in equal amounts. The mutant protein was expressed with 0.5% efficiency, as compared to wild type. Mutant and wild type mRNAs were translated in vitro. Wild type transferase is processed by microsomes, no processing of the mutant protein was observed.
Seppen
J
J
Department of Gastrointestinal and Liver Diseases, Academic Medical Centre, Amsterdam, The Netherlands. J.SEPPEN@AMC.UVA.NL
Steenken
E
E
Lindhout
D
D
Bosma
P J
PJ
Elferink
R P
RP
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003414:Crigler-Najjar Syndrome / Q000201:enzymology / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D015870:Gene Expression; D005808:Genes, Recessive; D014453:Glucuronosyltransferase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D006932:Hyperbilirubinemia / Q000201:enzymology / Q000235:genetics; D008099:Liver / Q000201:enzymology*; D008969:Molecular Sequence Data; D017354:Point Mutation; D014176:Protein Biosynthesis; D021382:Protein Sorting Signals / Q000737:chemistry / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017421:Sequence Analysis; D014158:Transcription, Genetic; D014162:Transfection
D021382:Protein Sorting Signals; D011994:Recombinant Proteins; D014453:Glucuronosyltransferase