Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

RAD21 mutations cause a human cohesinopathy.

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.

Pubmed ID: 22633399


  • Deardorff MA
  • Wilde JJ
  • Albrecht M
  • Dickinson E
  • Tennstedt S
  • Braunholz D
  • Mönnich M
  • Yan Y
  • Xu W
  • Gil-Rodríguez MC
  • Clark D
  • Hakonarson H
  • Halbach S
  • Michelis LD
  • Rampuria A
  • Rossier E
  • Spranger S
  • Van Maldergem L
  • Lynch SA
  • Gillessen-Kaesbach G
  • Lüdecke HJ
  • Ramsay RG
  • McKay MJ
  • Krantz ID
  • Xu H
  • Horsfield JA
  • Kaiser FJ


American journal of human genetics

Publication Data

June 8, 2012

Associated Grants

  • Agency: NICHD NIH HHS, Id: K08 HD055488
  • Agency: NICHD NIH HHS, Id: K08HD055488
  • Agency: NICHD NIH HHS, Id: P01 HD052860

Mesh Terms

  • Animals
  • Cell Cycle Proteins
  • Cell Line
  • Cell Survival
  • Chromosomal Proteins, Non-Histone
  • Cognition Disorders
  • Comet Assay
  • Craniofacial Abnormalities
  • DNA Damage
  • De Lange Syndrome
  • Ectromelia
  • Gene Dosage
  • Genome, Human
  • Humans
  • Hypertelorism
  • Micronucleus Tests
  • Mutation
  • Mutation, Missense
  • Nuclear Proteins
  • Phosphoproteins
  • Sister Chromatid Exchange
  • Two-Hybrid System Techniques
  • Zebrafish