RECQL4 Regulates p53 Function In Vivo During Skeletogenesis

J Bone Miner Res. 2015 Jun;30(6):1077-89. doi: 10.1002/jbmr.2436.


RECQ DNA helicases play critical roles in maintaining genomic stability, but their role in development has been less well studied. Rothmund-Thomson syndrome, RAPADILINO, and Baller-Gerold syndrome are rare genetic disorders caused by mutations in the RECQL4 gene. These patients have significant skeletal developmental abnormalities including radial ray, limb and craniofacial defects. To investigate the role of Recql4 in the developing skeletal system, we generated Recql4 conditional knockout mice targeting the skeletal lineage. Inactivation of Recql4 using the Prx1-Cre transgene led to limb abnormalities and craniosynostosis mimicking the major bone findings in human RECQL4 patients. These Prx1-Cre(+) ;Recql4(fl/fl) mice as well as Col2a1-Cre(+) ;Recql4(fl/fl) mice exhibited growth plate defects and an increased p53 response in affected tissues. Inactivation of Trp53 in these Recql4 mutants resulted in genetic rescue of the skeletal phenotypes, indicating an in vivo interaction between Recql4 and Trp53, and p53 activation as an underlying mechanism for the developmental bone abnormalities in RECQL4 disorders. Our findings show that RECQL4 is critical for skeletal development by modulating p53 activity in vivo.

Keywords: RECQL4; Rothmund-Thomson syndrome; cartilage; genetic animal models; skeletal development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anal Canal / abnormalities
  • Anal Canal / metabolism
  • Anal Canal / pathology
  • Animals
  • Bone Development*
  • Craniosynostoses / genetics
  • Craniosynostoses / metabolism
  • Craniosynostoses / pathology
  • Dwarfism / genetics
  • Dwarfism / metabolism
  • Dwarfism / pathology
  • Heart Septal Defects, Atrial / genetics
  • Heart Septal Defects, Atrial / metabolism
  • Heart Septal Defects, Atrial / pathology
  • Humans
  • Limb Deformities, Congenital / genetics
  • Limb Deformities, Congenital / metabolism
  • Limb Deformities, Congenital / pathology
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Patella / abnormalities
  • Patella / metabolism
  • Patella / pathology
  • Radius / abnormalities
  • Radius / metabolism
  • Radius / pathology
  • RecQ Helicases / genetics
  • RecQ Helicases / metabolism*
  • Rothmund-Thomson Syndrome / genetics
  • Rothmund-Thomson Syndrome / metabolism
  • Rothmund-Thomson Syndrome / pathology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Tumor Suppressor Protein p53
  • RecQ Helicases

Supplementary concepts

  • Craniosynostosis radial aplasia syndrome
  • Rapadilino syndrome