Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA

Abstract

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 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 analyzed 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.

Nicotinamide adenine dinucleotide (NAD)–regulated DNA methylation alters CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus

“…The correlation between CTCF occupancy and BDNF expression in cortical neurons led us to test whether cohesin was also critical for BDNF transcription. We focused on the core cohesin component SMC1 because the mutations found in Cornelia de Lange syndrome patients are consistent with a loss of function (31) and were therefore likely to be mimicked by SMC1 knockdown. SMC1 was depleted in cortical neurons by infecting with SMC1 small interfering RNA (siRNA) lentivirus.…”

Clinical utility gene card for: Cornelia de Lange syndrome

“…Moreover, 33 larger deletions and one balanced translocation have been reported as well. A much smaller percentage of patients (~4-6%) have mutations in the cohesin complex gene SMC1A, [6][7][8] in which 34 mutations have been identified so far, 9 including missense mutations (82%) or in-frame deletions (18%). No frameshift or nonsense mutations have been reported in this gene, possibly because they are lethal or lead to a different yet unrecognisable phenotype.…”

Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum

“…The hinge dimerization domain and the crucial functional motifs of the N-and C-terminal ABC cassettes are spared. Interference with cohesin binding to DNA has been demonstrated for SMC1A mutations mapping to the coiled-coil/hinge junctions, and a trend toward increased sensitivity to DNA damage has been described in most investigated patients' cell lines [Revenkova et al, 2009;Gimigliano et al, 2012]. In comparison with NIPBL, the clinical spectrum underpinned by SMC1A mutations generally includes fewer structural anomalies, no upper limb reduction, milder facial dysmorphisms, and attenuated growth delay.…”

“…Recurrent mutations could delineate clusters for genotype-phenotype correlations that may either predict disease outcome and evolution, or disclose the actions of modifiers. Individuals carrying novel mutations could enhance the understanding of the mechanisms by which altered SMC1A proteins dysregulate multiple downstream genes [Revenkova et al, 2009;Gimigliano et al, 2012;Horsfield et al, 2012].…”