PUBLICATION

RAD21 Mutations Cause a Human Cohesinopathy

Authors
Deardorff, M.A., Wilde, J.J., Albrecht, M., Dickinson, E., Tennstedt, S., Braunholz, D., Mönnich, M., Yan, Y., Xu, W., Gil-Rodríguez, M.C., Clark, D., Hakonarson, H., Halbach, S., Michelis, L.D., Rampuria, A., Rossier, E., Spranger, S., Van Maldergem, L., Lynch, S.A., Gillessen-Kaesbach, G., Lüdecke, H.J., Ramsay, R.G., McKay, M.J., Krantz, I.D., Xu, H., Horsfield, J.A., and Kaiser, F.J.
ID
ZDB-PUB-120529-48
Date
2012
Source
American journal of human genetics   90(6): 1014-1027 (Journal)
Registered Authors
Dickinson, Emma, Horsfield, Jules, Monnich, Maren
Keywords
none
MeSH Terms
  • Animals
  • Cell Cycle Proteins/genetics*
  • Cell Line
  • Cell Survival
  • Chromosomal Proteins, Non-Histone/genetics*
  • Cognition Disorders/genetics
  • Comet Assay/methods
  • Craniofacial Abnormalities/genetics
  • DNA Damage
  • De Lange Syndrome/genetics
  • Ectromelia/genetics
  • Gene Dosage
  • Genome, Human
  • Humans
  • Hypertelorism/genetics
  • Micronucleus Tests
  • Mutation*
  • Mutation, Missense
  • Nuclear Proteins/genetics*
  • Phosphoproteins/genetics*
  • Sister Chromatid Exchange
  • Two-Hybrid System Techniques
  • Zebrafish
PubMed
22633399 Full text @ Am. J. Hum. Genet.
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.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping