title: Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction.
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 NIBPL-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 NIBPL 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.
authors.affiliation: Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Braunholz
authors.forename: Melanie
authors.initials: M
authors.lastname: Hullings
authors.forename: María Concepcion
authors.initials: MC
authors.lastname: Gil-Rodríguez
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Fincher
authors.forename: Mark B
authors.initials: MB
authors.lastname: Mallozzi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Loy
authors.forename: Melanie
authors.initials: M
authors.lastname: Albrecht
authors.forename: Maninder
authors.initials: M
authors.lastname: Kaur
authors.forename: Janusz
authors.initials: J
authors.lastname: Limon
authors.forename: Abhinav
authors.initials: A
authors.lastname: Rampuria
authors.forename: Dinah
authors.initials: D
authors.lastname: Clark
authors.forename: Antonie
authors.initials: A
authors.lastname: Kline
authors.forename: Andreas
authors.initials: A
authors.lastname: Dalski
authors.forename: Juliane
authors.initials: J
authors.lastname: Eckhold
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wierzba
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
mesh_terms: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D003635:De Lange Syndrome / Q000235:genetics* / Q000378:metabolism*; D019066:Facies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D020125:Mutation, Missense; D010641:Phenotype; D011485:Protein Binding / Q000235:genetics; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C515655:MAU2 protein, human; C487465:NIPBL protein, human; D011506:Proteins