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

Nature Genetics volume 24, pages 438441 (2000) | Download Citation

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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 reported1. 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 (Dll3). Dll3 is mutated3 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 skeleton.

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Acknowledgements

We thank the families for cooperation; K. Maruthainar, K. Dewar and B. Birren for undertaking sequencing efforts; and the management and laboratory staff of The Nazareth Hospital, Israel for their help. This work was supported by the British Scoliosis Research Foundation, the Medical Research Council (UK), Action Research, the Skeletal Dysplasia Group (UK), the Children's Research Fund, the Darlington Charitable Trust, the Royal Devon & Exeter NHS Healthcare Trust and the University of Exeter. The assistance of the DNA Laboratories of the West Midlands Regional Genetics Service, Birmingham, the Yorkshire Regional Genetics Service, Leeds and the Kennedy-Galton Centre, London is appreciated. K.K. is supported by a Hitchings-Elion Fellowship of the Burroughs Wellcome Fund.

Author information

Author notes

    • Michael P. Bulman
    •  & Kenro Kusumi

    These authors contributed equally to this work.

Affiliations

  1. Molecular Genetics, School of Postgraduate Medicine and Health Sciences, Barrack Road, Exeter, UK

    • Michael P. Bulman
    • , Timothy M. Frayling
    • , Andrew T. Hattersley
    •  & Sian Ellard
  2. Division of Developmental Neurobiology, National Institute for Medical Research, The Ridgeway, London, UK.

    • Kenro Kusumi
    •  & Robb Krumlauf
  3. Clinical Genetics Unit, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.

    • Carole McKeown
  4. Kennedy Galton Centre, Northwick Park and St. Mark's Trust, Harrow, Middlesex, UK.

    • Christine Garrett
  5. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

    • Eric S. Lander
  6. Clinical Genetics, Royal Devon & Exeter Hospital, Barrack Road, Exeter, UK.

    • Peter D. Turnpenny

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Correspondence to Peter D. Turnpenny.

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DOI

https://doi.org/10.1038/74307

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