Mutations in Cohesin Complex Members SMC3 and SMC1A Cause a Mild Variant of Cornelia de Lange Syndrome with Predominant Mental Retardation

Abstract

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.

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

“…Mutations in SMC1A and SMC3 result in a phenotype with few structural anomalies, but moderate-to-severe mental retardation. [11][12][13][14] NIPBL function The NIPBL gene encodes a highly conserved protein, NIPBL or delangin, which contains HEAT-repeat protein interaction motifs, a glutamine-rich domain and a predicted bipartite nuclear localization signal. 6,8,15 Upon the identification of its role in CdLS, it was noted to have homology to Drosophila Nipped-B, 16 identified as a transcriptional regulator, and yeast Scc2, a key component of sister chromatid cohesion.…”

“…8,12 Patients were screened for mutations in MAU2 by sequencing of genomic DNA or by high-resolution melt curve analysis. Primer sequences and PCR conditions are available upon request.…”

Functional links between Drosophila Nipped-B and cohesin in somatic and meiotic cells

“…Indeed, Nipped-B NC71 and Nipped-B NC78 both affect conserved residues adjacent or very close to conserved residues affected by CdLS-causing mutations, and thus the CdLS mutations are likely to have dominant effects on gene expression similar to Nipped-B NC71 and Nipped-B NC78 . The structural similarity between Nipped-B NC71 and Nipped-B NC78 and the NIPBL mutations provides a link to cohesin in human development because like the NIPBL HEAT repeat mutations, missense mutations in the Smc1 and Smc3 cohesin subunits also cause CdLS (Deardorff et al 2007;Musio et al 2006). …”

Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome

“…Cornelia de Lange syndrome (CdLS) is caused by heterozygous loss-of-function mutations in the Nipped-B-Like (NIPBL) ortholog of Nipped-B and, in a few cases, by viable missense mutations in the Smc1A or Smc3 cohesin subunit genes (Deardorff et al 2007;Krantz et al 2004;Musio et al 2006;Tonkin et al 2004). CdLS patients display slow growth, mental retardation, and defects in limbs and organs (Dorsett 2007;Jackson et al 1993;Strachan 2005).…”