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

Michael P. Bulman, Kenro Kusumi, Timothy M. Frayling, Carole McKeown, Christine Garrett, Eric S. Lander, Robb Krumlauf, Andrew T. Hattersley, Sian Ellard, Peter D. Turnpenny

Research output: Contribution to journalArticle

278 Citations (Scopus)

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 (ref. 2) that is homologous with a mouse region containing a gene encoding the Notch ligand delta-like 3 (DII3). DII3 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 so 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 skeleton.

Original languageEnglish (US)
Pages (from-to)438-441
Number of pages4
JournalNature Genetics
Volume24
Issue number4
DOIs
StatePublished - Apr 2000
Externally publishedYes

Fingerprint

Mutation
Ribs
Missense Mutation
Epidermal Growth Factor
Skeleton
Glycine
Genes
Chromosomes
X-Rays
Ligands
Phenotype
Jarcho-Levin syndrome

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., ... Turnpenny, P. D. (2000). Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nature Genetics, 24(4), 438-441. https://doi.org/10.1038/74307

Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. / Bulman, Michael P.; Kusumi, Kenro; Frayling, Timothy M.; McKeown, Carole; Garrett, Christine; Lander, Eric S.; Krumlauf, Robb; Hattersley, Andrew T.; Ellard, Sian; Turnpenny, Peter D.

In: Nature Genetics, Vol. 24, No. 4, 04.2000, p. 438-441.

Research output: Contribution to journalArticle

Bulman, MP, Kusumi, K, Frayling, TM, McKeown, C, Garrett, C, Lander, ES, Krumlauf, R, Hattersley, AT, Ellard, S & Turnpenny, PD 2000, 'Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis', Nature Genetics, vol. 24, no. 4, pp. 438-441. https://doi.org/10.1038/74307
Bulman, Michael P. ; Kusumi, Kenro ; Frayling, Timothy M. ; McKeown, Carole ; Garrett, Christine ; Lander, Eric S. ; Krumlauf, Robb ; Hattersley, Andrew T. ; Ellard, Sian ; Turnpenny, Peter D. / Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. In: Nature Genetics. 2000 ; Vol. 24, No. 4. pp. 438-441.
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