Spectrum and consequences of SMC1A mutations: The unexpected involvement of a core component of cohesin in human disease

SMC1A encodes a structural component of the cohesin complex, which is necessary for sister chromatid cohesion. In addition to its canonical role, cohesin has been shown to be involved in gene expression regulation and maintenance of genome stability. Recently, it has been demonstrated that mutations in the SMC1A gene are responsible for Cornelia de Lange syndrome (CdLS). CdLS is a genetically heterogeneous multisystem developmental disorder with variable expressivity, typically characterized by consistent facial dysmorphia, upper extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, gastrointestinal abnormalities, and other systemic involvement. SMC1A mutations have also been identified in colorectal cancers. So far a total of 26 different mutations of the SMC1A gene have been reported. All mutations reported to date are either missense or small in‐frame deletions that maintain the open reading frame and presumably result in a protein with residual function. The mutations involve all domains of the protein but appear to cluster in key functional loci. At the functional level, elucidation of the effects that specific SMC1A mutations have on cohesin activity will be necessary to understand the etiopathology of CdLS and its possible involvement in tumorigenesis. In this review, we summarize the current knowledge of SMC1A mutations. Hum Mutat 30:1–6, 2009. © 2009 Wiley‐Liss, Inc.