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Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities of the liver, heart, eyes, vertebrae, and face. Mutations in the JAG1 (Jagged 1) gene, coding a ligand in the evolutionarily conserved Notch signaling pathway, are responsible for AGS. Here we present sixteen different JAG1 gene mutations, among them twelve novel, not described previously. Seven frameshift: c. 172_178del7 (p.Ala58fs), c.509delT (p.Leu170fs), c.1197delG (p.Val399fs), c.1485_1486delCT (p.Pro495fs), c.1809_1810insTGGG (p.Lys604fs), c.2122_2125delCAGT (p.Gln708fs), c.2753delT (p.Ile918fs); five nonsense: c.383GA (p.Trp128X), c.496CT (p.Glu166X), c.841CT (p.Gln281X), c.1207CT (p.Gln403X), c.1603CT (p.Gln535X); two splice site: c.388-1GC, c.3048+1_3048+2insG and two missense mutations: c.359TA (p.Ile120Asn), c.560GA (p.Cys187Tyr) were found. Forty percent of the changes were identified in exons 2 and 4, the remaining mutations are distributed along the entire coding sequence of the gene. Seventy-five percent of the mutations lead to creation of premature termination codons. Family studies revealed that the specific mutations were inherited in 3 out of 11 investigated cases. No correlation between genotype and phenotype was observed.

Alagille syndrome (AGS) is an autosomal dominant disorder characterized by five major symptoms: cholestasis, vertebral deformity, heart malformations, ocular defects and peculiar facial appearance. The previously described Jagged1 (JAG1) gene on chromosome 20p12 has been identified as being responsible for AGS. JAG1 encodes a transmembrane protein acting as ligand for the evolutionarily conserved Notch signaling pathway. Here we report 36 novel mutations in the JAG1 gene. We identified 12 novel deletions, 4 insertions, 8 missense, 7 nonsense and 5 splice site mutations. All mutations map to the sequence encoding the extracellular part of the Jagged1 protein. The mutations spread over the entire gene with slightly increased rates in exons 2 to 6 and exon 23 and 24. Eight novel missense mutations map to the Delta-Serrate-Lag2 (DSL) domain and adjacent sequences which are important for ligand-receptor interaction. Inheritance was determined in 27 families. Sixteen mutations (55%) were de novo and eleven mutations (45%) were transmitted. Altogether 226 different JAG1 mutations have been described in association with AGS, including our novel 36 mutations. AGS variants are spread over the entire gene with only a few mutations in exon 26. A relatively high number of mutations are clustered in exons 2 to 6. This sequence region shows high interspecies conservation and encodes the Notch receptor-binding region (DSL domain).

Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities of the liver, heart, eyes, vertebrae, and face. Mutations in the JAG1 (Jagged 1) gene, coding a ligand in the evolutionarily conserved Notch signaling pathway, are responsible for AGS. Here we present sixteen different JAG1 gene mutations, among them twelve novel, not described previously. Seven frameshift: c. 172_178del7 (p.Ala58fs), c.509delT (p.Leu170fs), c.1197delG (p.Val399fs), c.1485_1486delCT (p.Pro495fs), c.1809_1810insTGGG (p.Lys604fs), c.2122_2125delCAGT (p.Gln708fs), c.2753delT (p.Ile918fs); five nonsense: c.383G>A (p.Trp128X), c.496C>T (p.Glu166X), c.841C>T (p.Gln281X), c.1207C>T (p.Gln403X), c.1603C>T (p.Gln535X); two splice site: c.388-1G>C, c.3048+1_3048+2insG and two missense mutations: c.359T>A (p.Ile120Asn), c.560G>A (p.Cys187Tyr) were found. Forty percent of the changes were identified in exons 2 and 4, the remaining mutations are distributed along the entire coding sequence of the gene. Seventy-five percent of the mutations lead to creation of premature termination codons. Family studies revealed that the specific mutations were inherited in 3 out of 11 investigated cases. No correlation between genotype and phenotype was observed.

Alagille syndrome (AGS) is an autosomal dominant disorder characterized by five major symptoms: cholestasis, vertebral deformity, heart malformations, ocular defects and peculiar facial appearance. The previously described Jagged1 (JAG1) gene on chromosome 20p12 has been identified as being responsible for AGS. JAG1 encodes a transmembrane protein acting as ligand for the evolutionarily conserved Notch signaling pathway. Here we report 36 novel mutations in the JAG1 gene. We identified 12 novel deletions, 4 insertions, 8 missense, 7 nonsense and 5 splice site mutations. All mutations map to the sequence encoding the extracellular part of the Jagged1 protein. The mutations spread over the entire gene with slightly increased rates in exons 2 to 6 and exon 23 and 24. Eight novel missense mutations map to the Delta-Serrate-Lag2 (DSL) domain and adjacent sequences which are important for ligand-receptor interaction. Inheritance was determined in 27 families. Sixteen mutations (55%) were de novo and eleven mutations (45%) were transmitted. Altogether 226 different JAG1 mutations have been described in association with AGS, including our novel 36 mutations. AGS variants are spread over the entire gene with only a few mutations in exon 26. A relatively high number of mutations are clustered in exons 2 to 6. This sequence region shows high interspecies conservation and encodes the Notch receptor-binding region (DSL domain). © 2002 Wiley-Liss, Inc.