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Human Molecular Genetics Advance Access originally published online on April 17, 2008
Human Molecular Genetics 2008 17(14):2244-2254; doi:10.1093/hmg/ddn125
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome

Dobrawa Napierala1, Kathy Sam1, Roy Morello1, Qiping Zheng1,{dagger}, Elda Munivez1, Ramesh A. Shivdasani3 and Brendan Lee1,2,*

1 Department of Molecular and Human Genetics 2 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA 3 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

* To whom correspondence should be addressed at: Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Tel: +1 7137988835; Fax: +1 7137985168; Email: blee{at}bcm.edu

Received February 20, 2008; Accepted April 11, 2008

Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant craniofacial and skeletal dysplasia that is caused by mutations involving the TRPS1 gene. Patients with TRPS have short stature, hip abnormalities, cone-shaped epiphyses and premature closure of growth plates reflecting defects in endochondral ossification. The TRPS1 gene encodes for the transcription factor TRPS1 that has been demonstrated to repress transcription in vitro. To elucidate the molecular mechanisms underlying skeletal abnormalities in TRPS, we analyzed Trps1 mutant mice (Trps1{Delta}GT mice). Analyses of growth plates demonstrated delayed chondrocyte differentiation and accelerated mineralization of perichondrium in Trps1 mutant mice. These abnormalities were accompanied by increased Runx2 and Ihh expression and increased Indian hedgehog signaling. We demonstrated that Trps1 physically interacts with Runx2 and represses Runx2-mediated trans-activation. Importantly, generation of Trps1{Delta}GT/+;Runx2+/– double heterozygous mice rescued the opposite growth plate phenotypes of single mutants, demonstrating the genetic interaction between Trps1 and Runx2 transcription factors. Collectively, these data suggest that skeletal dysplasia in TRPS is caused by dysregulation of chondrocyte and perichondrium development partially due to loss of Trps1 repression of Runx2.

{dagger} Present address: Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL 60612, USA.


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