title: Jagged-1 mutation analysis in Italian Alagille syndrome patients.
abstract: Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities affecting the liver, heart, eyes, vertebrae, and craniofacial region. The Jagged-1 (JAG1) gene, which encodes a ligand of Notch, has recently been found mutated in AGS. In this study, mutation analysis of the JAG1 gene performed on 20 Italian AGS patients led to the identification of 15 different JAG1 mutations, including a large deletion of the 20p12 region, six frameshift, three nonsense, three splice-site, and two missense mutations. The two novel missense mutations were clustered in the 5' region, while the remaining mutations were scattered throughout the gene. The spectrum of mutations in Italian patients was similar to that previously reported. We also studied in detail a complex splice site mutation, 3332dupl8bp, which was shown to lead to an abnormal JAG1 mRNA, resulting in a premature stop codon. With the exception of the missense mutations, the majority of the JAG1 mutations are therefore likely to produce truncated proteins. Since the phenotype of the patient with a complete deletion of the JAG1 gene is indistinguishable from that of patients with intragenic mutations, our study further supports the hypothesis that haploinsufficiency is the most common mechanism involved in AGS pathogenesis. Furthermore, our data confirmed the absence of a correlation between the genotype of the JAG1 gene and the AGS phenotype.
authors.affiliation: Istituto di Ricerca sulle Talassemie ed Anemie Mediterranee CNR, Cagliari, Italy. pilia@vaxca1.unica.it
authors.forename: G
authors.initials: G
authors.lastname: Pilia
authors.forename: M
authors.initials: M
authors.lastname: Uda
authors.forename: D
authors.initials: D
authors.lastname: Macis
authors.forename: F
authors.initials: F
authors.lastname: Frau
authors.forename: L
authors.initials: L
authors.lastname: Crisponi
authors.forename: F
authors.initials: F
authors.lastname: Balli
authors.forename: C
authors.initials: C
authors.lastname: Barbera
authors.forename: C
authors.initials: C
authors.lastname: Colombo
authors.forename: T
authors.initials: T
authors.lastname: Frediani
authors.forename: R
authors.initials: R
authors.lastname: Gatti
authors.forename: R
authors.initials: R
authors.lastname: Iorio
authors.forename: M G
authors.initials: MG
authors.lastname: Marazzi
authors.forename: M
authors.initials: M
authors.lastname: Marcellini
authors.forename: S
authors.initials: S
authors.lastname: Musumeci
authors.forename: G
authors.initials: G
authors.lastname: Nebbia
authors.forename: P
authors.initials: P
authors.lastname: Vajro
authors.forename: G
authors.initials: G
authors.lastname: Ruffa
authors.forename: L
authors.initials: L
authors.lastname: Zancan
authors.forename: A
authors.initials: A
authors.lastname: Cao
authors.forename: S
authors.initials: S
authors.lastname: DeVirgilis
mesh_terms: D016738:Alagille Syndrome / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D002648:Child; D018389:Codon, Nonsense; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007558:Italy; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D018389:Codon, Nonsense; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D000072099:Serrate-Jagged Proteins; D004247:DNA