Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation

Am J Hum Genet. 2007 Mar;80(3):485-94. doi: 10.1086/511888. Epub 2007 Jan 17.


Mutations in the cohesin regulators NIPBL and ESCO2 are causative of the Cornelia de Lange syndrome (CdLS) and Roberts or SC phocomelia syndrome, respectively. Recently, mutations in the cohesin complex structural component SMC1A have been identified in two probands with features of CdLS. Here, we report the identification of a mutation in the gene encoding the complementary subunit of the cohesin heterodimer, SMC3, and 14 additional SMC1A mutations. All mutations are predicted to retain an open reading frame, and no truncating mutations were identified. Structural analysis of the mutant SMC3 and SMC1A proteins indicate that all are likely to produce functional cohesin complexes, but we posit that they may alter their chromosome binding dynamics. Our data indicate that SMC3 and SMC1A mutations (1) contribute to approximately 5% of cases of CdLS, (2) result in a consistently mild phenotype with absence of major structural anomalies typically associated with CdLS, and (3) in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Cell Cycle Proteins / genetics*
  • Child
  • Chondroitin Sulfate Proteoglycans / genetics*
  • Chromosomal Proteins, Non-Histone / genetics*
  • Crystallography, X-Ray
  • DNA Mutational Analysis
  • De Lange Syndrome / diagnosis
  • De Lange Syndrome / genetics*
  • Female
  • Genetic Variation*
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics*
  • Phenotype
  • Protein Conformation
  • Sequence Homology, Amino Acid


  • Cell Cycle Proteins
  • Chondroitin Sulfate Proteoglycans
  • Chromosomal Proteins, Non-Histone
  • SMC3 protein, human
  • structural maintenance of chromosome protein 1

Associated data

  • PDB/1W1WA
  • PDB/1W1WB
  • RefSeq/NM_005445
  • RefSeq/NM_006306