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

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

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Child
  • Chromosomes, Human, Pair 19 / genetics
  • Cloning, Molecular
  • Conserved Sequence
  • DNA Mutational Analysis
  • Dysostoses / diagnostic imaging
  • Dysostoses / etiology
  • Dysostoses / genetics*
  • Female
  • Genetic Linkage
  • Humans
  • Infant
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins / genetics*
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Protein Structure, Tertiary / genetics
  • Radiography
  • Receptors, Notch
  • Ribs / abnormalities*
  • Ribs / diagnostic imaging
  • Scoliosis / diagnostic imaging
  • Scoliosis / etiology
  • Scoliosis / genetics*
  • Sequence Homology, Amino Acid
  • Signal Transduction / genetics
  • Spine / abnormalities*
  • Spine / diagnostic imaging

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch
  • delta protein

Associated data

  • GENBANK/AF068865
  • GENBANK/AF241367
  • GENBANK/AF241368
  • GENBANK/AF241369
  • GENBANK/AF241370
  • GENBANK/AF241371
  • GENBANK/AF241372
  • GENBANK/AF241373