Abstract
Cornelia de Lange syndrome (CdLS) is a multiple malformation disorder characterized by dysmorphic facial features, mental retardation, growth delay and limb reduction defects1,2. We indentified and characterized a new gene, NIPBL, that is mutated in individuals with CdLS and determined its structure and the structures of mouse, rat and zebrafish homologs. We named its protein product delangin. Vertebrate delangins have substantial homology to orthologs in flies, worms, plants and fungi, including Scc2-type sister chromatid cohesion proteins, and D. melanogaster Nipped-B. We propose that perturbed delangin function may inappropriately activate DLX genes, thereby contributing to the proximodistal limb patterning defects in CdLS. Genome analyses typically identify individual delangin or Nipped-B-like orthologs in diploid animal and plant genomes. The evolution of an ancestral sister chromatid cohesion protein to acquire an additional role in developmental gene regulation suggests that there are parallels between CdLS and Roberts syndrome.
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Acknowledgements
This paper is dedicated to the memory of F. Strachan (1921–2004). We thank many of our current Newcastle colleagues, especially S. Zwolinsky and J. Wolstenholme, for discussions, carrying out chromosome-banding analyses and conducting the premature centromere separation assay; H. Peters and D. Henderson for contributions to analysis of our expression data; S. Humphray for supplying fosmid clones; L. Jackson for facilitating the collaboration between M.B. and the Newcastle group; I. Krantz for discussions; A. Peaford and colleagues for their support; M. Walasek, M. Ireland and many other clinical geneticists for providing blood samples from individuals with CdLS and access to phenotype data; many individuals with CdLS and their families for their generosity; and previous members of the Newcastle CdLS research team, notably M. Smith, P. J. A. Eichhorn and B. Imamwerdi, for their earlier contributions. We thank the UK Community Fund and previously Action Research for providing funding for this project and the MRC-Wellcome Human Developmental Biology Resource for supplying human embryonic tissue samples.
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Tonkin, E., Wang, TJ., Lisgo, S. et al. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet 36, 636–641 (2004). https://doi.org/10.1038/ng1363
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DOI: https://doi.org/10.1038/ng1363
