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).