Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome

PLoS Genet. 2009 Sep;5(9):e1000650. doi: 10.1371/journal.pgen.1000650. Epub 2009 Sep 18.


Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75-80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only approximately 30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/- mice and in individuals with CdLS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Bone Development
  • Bone and Bones / abnormalities
  • Bone and Bones / pathology
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Cycle Proteins
  • Craniofacial Abnormalities / complications
  • Craniofacial Abnormalities / genetics
  • Craniofacial Abnormalities / pathology
  • Craniofacial Abnormalities / physiopathology
  • De Lange Syndrome / complications
  • De Lange Syndrome / genetics*
  • De Lange Syndrome / pathology*
  • De Lange Syndrome / physiopathology
  • Disease Models, Animal
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / pathology
  • Gene Expression Regulation*
  • Heart Defects, Congenital / complications
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / pathology
  • Heart Defects, Congenital / physiopathology
  • Heterozygote*
  • Mice
  • Mutation / genetics
  • Nervous System Malformations / complications
  • Nervous System Malformations / genetics
  • Nervous System Malformations / physiopathology
  • Organ Specificity / genetics*
  • Phenotype
  • Sister Chromatid Exchange
  • Survival Analysis
  • Transcription Factors / genetics*
  • Transcription, Genetic*


  • Cadherins
  • Cell Cycle Proteins
  • Nipbl protein, mouse
  • Transcription Factors