TY - JOUR
T1 - Jagged-1 mutation analysis in Italian Alagille syndrome patients
AU - Pilia, Giuseppe
AU - Uda, Manuela
AU - Macis, Dolores
AU - Frau, Fulvia
AU - Crisponi, Laura
AU - Balli, Fiorella
AU - Barbera, Cristiana
AU - Colombo, Carla
AU - Frediani, Tullio
AU - Gatti, Rosanna
AU - Iorio, Raffaele
AU - Marazzi, M. Grazia
AU - Marcellini, Matilde
AU - Musumeci, Salvatore
AU - Nebbia, Gabriella
AU - Vajro, Pietro
AU - Ruffa, Giuseppe
AU - Zancan, Lucia
AU - Cao, Antonio
AU - De Virgilis, Stefano
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
KW - AGS
KW - Alagille syndrome
KW - Genotype-phenotype
KW - JAG1
KW - Jagged-1
UR - http://www.scopus.com/inward/record.url?scp=0032706856&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032706856&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1098-1004(199911)14:5<394::AID-HUMU5>3.0.CO;2-1
DO - 10.1002/(SICI)1098-1004(199911)14:5<394::AID-HUMU5>3.0.CO;2-1
M3 - Article
C2 - 10533065
AN - SCOPUS:0032706856
VL - 14
SP - 394
EP - 400
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 5
ER -