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Human Molecular Genetics Advance Access published online on November 7, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn369
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

CORNELIA DE LANGE SYNDROME MUTATIONS IN SMC1A OR SMC3 AFFECT BINDING TO DNA

Ekaterina Revenkova1, Maria Luisa Focarelli2,3, Lucia Susani2,3, Marianna Paulis2,3, Maria Teresa Bassi4, Linda Mannini5, Annalisa Frattini2,3, Domenico Delia6, Ian Krantz7, Paolo Vezzoni2,3, Rolf Jessberger8 and Antonio Musio5,9,*

1 Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, USA 2 Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Segrate (Mi), Italy 3 Istituto Clinico Humanitas, Rozzano (Mi), Italy 4 E. Medea Scientific Institute, Laboratory of Molecular Biology, Bosisio Parini (Lc), Italy, 5 Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Pisa, Italy 6 Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy 7 Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, USA 8 Institute of Physiological Chemistry, Dresden University of Technology, Dresden, Germany 9 Istituto Toscano Tumori, Florence, Italy

* To whom correspondence may be addressed Tel: +39 0503152776 Fax: +39 0503153973 Email: antonio.musio{at}itb.cnr.it

Received September 16, 2008; Revised November 4, 2008; Accepted November 4, 2008

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous developmental disorder characterized by facial dysmorphia, upper-limb malformations, growth and cognitive retardation. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A and SMC3 are present in about 65% of CdLS patients. In addition to their canonical roles in chromosome segregation, the cohesin proteins are involved in other biological processes such as regulation of gene expression, DNA repair and maintenance of genome stability. To gain insights into the molecular basis of CdLS, we analysed the affinity of mutated SMC1A and SMC3 hinge domains for DNA. Mutated hinge dimers bind DNA with higher affinity than wild type proteins. SMC1A- and SMC3-mutated CdLS cell lines display genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. We propose that SMC1A and SMC3 CdLS mutations affect the dynamic association between SMC proteins and DNA, providing new clues to the underlying molecular cause of CdLS.


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