Abstract
The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a "cohesinopathy." Children with RAD21 mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in NIPBL, SMC1A, or SMC3, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development.
| Original language | English |
|---|---|
| Journal | American Journal of Human Genetics |
| Volume | 90 |
| Issue number | 6 |
| Pages (from-to) | 1014-1027 |
| Number of pages | 14 |
| ISSN | 0002-9297 |
| DOIs | |
| Publication status | Published - 08.06.2012 |
Funding
We are exceptionally grateful to the children and families who participated in this study as well as to the referring physicians and colleagues who have contributed samples and clinical information. We thank Maninder Kaur and Melanie Hullings for technical assistance and Pavel Lobachevsky and Goli Mostoufi-Moab for assistance with statistical analysis of the radiation-survival experiments. We are indebted to the continued support of the USA and International Cornelia de Lange Syndrome Foundations. This work was supported by National Institutes of Health grants K08HD055488 (from the National Institute of Child Health and Human Development [NICHD] to M.A.D.), P01 HD052860 (from the NICHD to I.D.K.), research grants from the USA CdLS Foundation, institutional funds from the Children's Hospital of Philadelphia, Cancer Council Victoria Australia grant 081219 (to H.X. and M.J.M.), Australian National Health and Medical Research Council project grant 1007659 (to R.G.R., H.X., and M.J.M.), Marsden grant UOO0713 (to E.D., M.M., and J.H.), funds from New Zealand Lottery Health Research (to E.D., M.M., and J.H.), Spanish Ministerio de Sanidad grant PI091422 (to M.C.G.-R.), and intramural funding of the University of Lübeck, Germany (“Schwerpunktprogramm: Medizinische Genetik,” to F.J.K. and G.G.-K.).
