1. Isolated NIPBL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction
- Author
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Andreas Dalski, Abhinav Rampuria, María Concepción Gil-Rodríguez, Gabriele Gillessen-Kaesbach, Frank J. Kaiser, Jolanta Wierzba, Melanie Hullings, Antonie D. Kline, Mark B. Mallozzi, Dinah Clark, Melanie Albrecht, Andreas Tzschach, Ian D. Krantz, Christopher T. Fincher, Elizabeth Loy, Matthew A. Deardorff, Juliane Eckhold, Janusz Limon, Raoul C.M. Hennekam, Maninder Kaur, Diana Braunholz, Amsterdam Neuroscience, Amsterdam Public Health, and Paediatrics
- Subjects
Cornelia de Lange Syndrome ,Mutation, Missense ,Cell Cycle Proteins ,Plasma protein binding ,Biology ,Article ,De Lange Syndrome ,Genetics ,medicine ,Missense mutation ,Humans ,Protein Interaction Domains and Motifs ,Genetics (clinical) ,Cohesin ,Facies ,Proteins ,NIPBL ,medicine.disease ,Phenotype ,Chromatin ,Establishment of sister chromatid cohesion ,DNA-Binding Proteins ,Intercellular Signaling Peptides and Proteins ,Corrigendum ,Protein Binding - Abstract
Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIPBL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2 interacting domain of NIPBL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS. European Journal of Human Genetics (2012) 20, 271-276; doi:10.1038/ejhg.2011.175; published online 21 September 2011
- Published
- 2012