title: Genetic heterogeneity of Crigler-Najjar syndrome type I: a study of 14 cases.
abstract: Crigler-Najjar syndrome type I (CN-I) is an autosomal recessive condition characterized by severe unconjugated hyperbilirubinemia caused by the lack of bilirubin-UDP-glucuronosyltransferase (B-UGT) activity in the liver. Two B-UGTs are coded for by a gene complex (UGT1) that maps to chromosome 2q37 and that also encodes two phenol-UDP-glucuronosyltransferases. Here, we report eleven mutations (including nine novel mutations) of the B-UGT1 gene in a large series of 14 unrelated CN-I children of various geographic origins: France (seven patients: A401P, Q357X, W335X, A368T, 1223insG, A291V, K426E, K437X); Portugal (two patients: G308E); Tunisia (two patients; Q357R); Turkey (one patient: S381R); italy (two siblings: S381R). Interestingly, 6/14 mutant alleles carried by unrelated probands of French ancestry bore the A401P mutation, indicating a founder effect; this effect is probably also present in Portugal, Turkey, and Tunisia. Since mutations occurred in exons 2-5 shared by all mRNAs species of the gene, a combined deficiency of B-UGT and P-UGT was observed in the liver of five patients in whom these activities were measured. The present study confirms that CN-I is genetically heterogeneous and suggests that different founder effects are involved in Western Europe, the Middle East, and North Africa.
authors.affiliation: Unité de Recherche sur les Handicaps Génétiques de l'Enfant, INSERM U393, Hôpital des Enfants Malades, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Labrune
authors.forename: A
authors.initials: A
authors.lastname: Myara
authors.forename: M
authors.initials: M
authors.lastname: Hadchouel
authors.forename: F
authors.initials: F
authors.lastname: Ronchi
authors.forename: O
authors.initials: O
authors.lastname: Bernard
authors.forename: F
authors.initials: F
authors.lastname: Trivin
authors.forename: N R
authors.initials: NR
authors.lastname: Chowdhury
authors.forename: J R
authors.initials: JR
authors.lastname: Chowdhury
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: M
authors.initials: M
authors.lastname: Odièvre
mesh_terms: D003414:Crigler-Najjar Syndrome / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational