Mutations in the human JAGGED1 gene cause Alagille syndrome, an autosomal dominant developmental disorder. The gene encodes a transmembrane protein which is a ligand of Notch receptors. We report 23 mutations in previously undescribed probands, including 15 novel mutations and 8 recurrent mutations. They map in the part of the gene encoding the extracellular part of the protein. Fifteen mutations are frameshifts and 8 are point mutations. They could give rise to truncated proteins (18/23, including 5 nonsense mutations). There are 2 splice defects, and the 3 missense mutations all cause loss or creation of cysteine residues in the Delta-Serrate-Lag2 domain or in EGF repeats. The inheritance was studied in 14 families, including those of 2 probands previously studied. Two mutations were transmitted from the father and 3 from the mother. Nine mutations were de novo, further confirmation that the majority of cases are sporadic.
Copyright 2001 Wiley-Liss, Inc.