TY - JOUR
T1 - Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction
AU - Braunholz, Diana
AU - Hullings, Melanie
AU - Gil-Rodríguez, María Concepcion
AU - Fincher, Christopher T.
AU - Mallozzi, Mark B.
AU - Loy, Elizabeth
AU - Albrecht, Melanie
AU - Kaur, Maninder
AU - Limon, Janusz
AU - Rampuria, Abhinav
AU - Clark, Dinah
AU - Kline, Antonie
AU - Eckhold, Juliane
AU - Tzschach, Andreas
AU - Hennekam, Raoul
AU - Gillessen-Kaesbach, Gabriele
AU - Wierzba, Jolanta
AU - Krantz, Ian D.
AU - Deardorff, Matthew A.
AU - Kaiser, Frank J.
PY - 2012/3/1
Y1 - 2012/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84857189905&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2011.175
DO - 10.1038/ejhg.2011.175
M3 - Journal articles
C2 - 21934712
AN - SCOPUS:84857189905
SN - 1018-4813
VL - 20
SP - 271
EP - 276
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 3
ER -