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. 2000 Apr;24(4):438-41.
doi: 10.1038/74307.

Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis

M P Bulman  1 , K Kusumi, T M Frayling, C McKeown, C Garrett, E S Lander, R Krumlauf, A T Hattersley, S Ellard, P D Turnpenny
Affiliations

Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis

M P Bulman et al. Nat Genet. 2000 Apr.

Abstract

Spondylocostal dysostosis (SD, MIM 277300) is a group of vertebral malsegmentation syndromes with reduced stature resulting from axial skeletal defects. SD is characterized by multiple 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 reported. Autosomal recessive SD maps to a 7.8-cM interval on chromosome 19q13.1-q13.3 that is homologous with a mouse region containing a gene encoding the Notch ligand delta-like 3 (Dll3). Dll3 is mutated in the X-ray-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 truncations within conserved extracellular domains. The third is a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor (EGF) repeat, which has revealed an important functional role for this domain. These represent the first mutations in a human Delta homologue, thus highlighting the critical role of the Notch signalling pathway and its components in patterning the mammalian axial

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