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.
Division of Genetics, The Children's Hospital of Philadelphia, PA 19104, USA. deardorff@email.chop.edu
Matthew A
MA
Deardorff
Jonathan J
JJ
Wilde
Melanie
M
Albrecht
Emma
E
Dickinson
Stephanie
S
Tennstedt
Diana
D
Braunholz
Maren
M
Mönnich
Yuqian
Y
Yan
Weizhen
W
Xu
María Concepcion
MC
Gil-Rodríguez
Dinah
D
Clark
Hakon
H
Hakonarson
Sara
S
Halbach
Laura Daniela
LD
Michelis
Abhinav
A
Rampuria
Eva
E
Rossier
Stephanie
S
Spranger
Lionel
L
Van Maldergem
Sally Ann
SA
Lynch
Gabriele
G
Gillessen-Kaesbach
Hermann-Josef
HJ
Lüdecke
Robert G
RG
Ramsay
Michael J
MJ
McKay
Ian D
ID
Krantz
Huiling
H
Xu
Julia A
JA
Horsfield
Frank J
FJ
Kaiser
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D003072:Cognition Disorders / Q000235:genetics; D020552:Comet Assay / Q000379:methods; D019465:Craniofacial Abnormalities / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins; D003635:De Lange Syndrome / Q000235:genetics; D004480:Ectromelia / Q000235:genetics; D018628:Gene Dosage; D015894:Genome, Human; D006801:Humans; D006972:Hypertelorism / Q000235:genetics; D015162:Micronucleus Tests; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D012854:Sister Chromatid Exchange; D020798:Two-Hybrid System Techniques; D015027:Zebrafish; D000097722:Cohesins
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000097722:Cohesins; C429022:RAD21 protein, human