Cornelia de Lange syndrome, cohesin, and beyond

Abstract

Cornelia de Lange syndrome (CdLS) (OMIM #122470, #300590 and #610759) is a dominant genetic disorder with multiple organ system abnormalities which is classically characterized by typical facial features, growth and mental retardation, upper limb defects, hirsutism, gastrointestinal and other visceral system involvement. Mutations in three cohesin proteins, a key regulator of cohesin, NIPBL, and two structural components of the cohesin ring SMC1A and SMC3, etiologically account for about 65% of individuals with CdLS. Cohesin controls faithful chromosome segregation during the mitotic and meiotic cell cycles. Multiple proteins in the cohesin pathway are also involved in additional fundamental biological events such as double-strand DNA break repair and long-range regulation of transcription. Moreover, chromosome instability was recently associated with defective sister chromatid cohesion in several cancer studies, and an increasing number of human developmental disorders is being reported to result from disruption of this pathway. Here, we will discuss the human disorders caused by alterations of cohesin function (termed 'cohesinopathies'), with an emphasis on the clinical manifestations of CdLS and mechanistic studies of the CdLS-related proteins.

Fig. 1

Clinical characteristics in Cornelia de Lange syndrome. (a) A severely affected 19-year-old man with protein truncating mutation in NIPBL. Note the characteristic facial features (arched eyebrows, synophrys, ptosis, anteverted nares, long philtrum, thin upper lip with down-turned corners and micrognathia) and severe asymmetrical defects of the forearms. (b) A mildly affected 9-year-old girl with a missense mutation in SMC1A. Note the more mild facial features and hand involvement (small with mild fifth finger clinodactyly).

Fig. 2

Cohesinopathies. Human disorders associated with mutations in cohesin subunits and accessory proteins of cohesin complex. SMC1A, SMC3, RAD21 and either SA1 or SA2 are the four major subunits of cohesin in somatic vertebrate cells. RAD21 crosslinks the head domains of SMC1A and SMC3 in an ATP-dependent manner, whereas RAD21 also binds to the fourth cohesin subunit SA1/SA2. NIPBL and MAU-2 form a complex and facilitate cohesin loading and unloading. Sister chromatid cohesion is established during S phase, mediated by sororin and ESCO1/ESCO2, after which PDS5 maintains cohesion through G2 phase. The removal of cohesin from the chromosome arms starts at prophase and is regulated by PLK1, Aurora B kinase, condensin I, and WAPL. During the metaphase-to-anaphase transition, the separase inhibitor securin is degraded by APC (anaphase-promoting complex), thereby activating separase which in turn cleaves centromeric cohesin as well as residual cohesin on the chromosome arms. This enables sister chromatid separation. Human disorders are listed corresponding to their disease causing genes in the cohesion pathway and the point in the cell cycle at which these respective genes are active. These disorders are further subclassified as developmental disorders and cancers. STAG3* is a cohesin subunit normally found in meiosis.