title: Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.
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
authors.affiliation: Molecular Genetics, School of Postgraduate Medicine and Health Sciences, Barrack Road, Exeter, UK.
authors.forename: M P
authors.initials: MP
authors.lastname: Bulman
authors.forename: K
authors.initials: K
authors.lastname: Kusumi
authors.forename: T M
authors.initials: TM
authors.lastname: Frayling
authors.forename: C
authors.initials: C
authors.lastname: McKeown
authors.forename: C
authors.initials: C
authors.lastname: Garrett
authors.forename: E S
authors.initials: ES
authors.lastname: Lander
authors.forename: R
authors.initials: R
authors.lastname: Krumlauf
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: P D
authors.initials: PD
authors.lastname: Turnpenny
mesh_terms: D000328:Adult; D000818:Animals; D002648:Child; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004413:Dysostoses / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics; D011859:Radiography; D051880:Receptors, Notch; D012272:Ribs / Q000002:abnormalities* / Q000000981:diagnostic imaging; D012600:Scoliosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics; D013131:Spine / Q000002:abnormalities* / Q000000981:diagnostic imaging
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C064045:delta protein