title: Spectrum of UGT1A1 mutations in Crigler-Najjar (CN) syndrome patients: identification of twelve novel alleles and genotype-phenotype correlation.
abstract: Crigler-Najjar syndrome types I and II (CN1 and CN2) are usually inherited as autosomal recessive conditions and are characterized by non-hemolytic unconjugated hyperbilirubinaemia. CN1 is the most severe form, associated with the absence of hepatic bilirubin-uridinediphosphoglucuronate glucuronosyltransferase (UGT1A1) activity. CN2 presents intermediate levels of hyperbilirubinaemia as a result of an incomplete deficiency of hepatic UGT1A1 activity. Here, we present the analysis of UGT1A1 gene in 31 unrelated Crigler-Najjar (CN) syndrome patients. This analysis allowed us to identify 22 mutations, 12 of which were not previously described, expanding the spectrum of known UGT1 mutations to 77. Novel mutations, considered pathogenic, including one nonsense mutation, two altered splice sites, one single base deletion and nine missense mutations were identified in coding exons of the UGT1A1gene and flanking introns. Several novel missense mutations localize in critical domain of UGT1A1 enzyme. In addition, the evaluation of Gilbert-type promoter of UGT1A1in Crigler-Najjar (CN) syndrome patients was performed. The polymorphisms of the promoter region can modify the UGT1A1 mutation phenotype. This study represents the molecular characterization of the largest cohort of Italian Crigler-Najjar Gilbert syndrome patients studied so far; increase the mutational spectrum of UGT1A1 allelic variants worldwide and provide a new insight useful for clinical diagnosis and genetic counseling.
authors.affiliation: Laboratory of Molecular Medicine, University of Foggia, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Servedio
authors.forename: Maria
authors.initials: M
authors.lastname: d'Apolito
authors.forename: Nunzia
authors.initials: N
authors.lastname: Maiorano
authors.forename: Barbara
authors.initials: B
authors.lastname: Minuti
authors.forename: Francesca
authors.initials: F
authors.lastname: Torricelli
authors.forename: Flavio
authors.initials: F
authors.lastname: Ronchi
authors.forename: Lucia
authors.initials: L
authors.lastname: Zancan
authors.forename: Silverio
authors.initials: S
authors.lastname: Perrotta
authors.forename: Pietro
authors.initials: P
authors.lastname: Vajro
authors.forename: Loredana
authors.initials: L
authors.lastname: Boschetto
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D001663:Bilirubin / Q000097:blood; D018389:Codon, Nonsense; D015331:Cohort Studies; D003241:Consanguinity; D003414:Crigler-Najjar Syndrome / Q000145:classification / Q000235:genetics*; D017523:Croatia / Q000208:ethnology; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D007558:Italy; D008297:Male; D009018:Morocco / Q000208:ethnology; D020125:Mutation, Missense; D010641:Phenotype; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics*; D017384:Sequence Deletion; D044465:White People / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D018389:Codon, Nonsense; D014453:Glucuronosyltransferase; D022821:RNA Splice Sites; D000099148:UGT1A1 Enzyme