Mutations in the human Delta homologue, DLL3, cause axial skeletal defectsin spondylocostal dysostosis

Spondylocostal dysostosis (SD, MIM 277300) is a group of vertebral malsegme ntation syndromes with reduced stature resulting from axial skeletal defect s. SD is characterized by mu[tiple hemivertebrae, rib fusions and deletions with a non-progressive kyphoscoliosis. Cases may be sporadic or familial, with both autosomal dominant and autosomal recessive modes of inheritance r eported(1). Autosomal recessive SD maps to a 7.8cM interval on chromosome 1 9q13.1-q13.3 (ref, 2) that is homologous with a mouse region containing a g ene encoding the Notch ligand delta-like 3 (DII3). DII3 is mutated(3) in th e Xray-induced mouse mutant pudgy (pu), causing a variety of vertebrocostal defects similar to SD phenotypes. Here we have cloned and sequenced human DLL3 to evaluate it as a candidate gene for SD and identified mutations in three autosomal recessive SD families. Two of the mutations predict truncat ions within conserved extracellular domains. The third is a missense mutati on in a highly conserved glycine residue of the fifth epidermal growth fact or (EGF) repeat, which has revealed an important functional role for this d omain. These represent the first mutations in a human Delta homologue, thus highlighting the critical role of the Notch signalling pathway and its com ponents in patterning the mammalian axial skeleton.