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

Matthew A. Deardorff, Maninder Kaur, Dinah Yaeger, Abhinav Rampuria, Sergey Korolev, Juan Pie, Concepcion Gil-Rodríguez, María Arnedo, Bart Loeys, Antonie D. Kline, Meredith Wilson, Kaj Lillquist, Victoria Siu, Feliciano J. Ramos, Antonio Musio, Laird S. Jackson, Dale Dorsett, Ian D. Krantz

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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 ∼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.

Original languageEnglish (US)
Pages (from-to)485-494
Number of pages10
JournalAmerican journal of human genetics
Volume80
Issue number3
DOIs
StatePublished - Mar 2007

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodríguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., & Krantz, I. D. (2007). Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation. American journal of human genetics, 80(3), 485-494. https://doi.org/10.1086/511888