Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

Research output: Contribution to journalArticlepeer-review


  • Hae Ryung Chang
  • Sung Yoon Cho
  • Jae Hoon Lee
  • Eunkyung Lee
  • Jieun Soo
  • Hye Ran Lee
  • Denise P Cavalcanti
  • Outi Mäkitie
  • Helena Valta
  • Katta M. Girisha
  • Chung Lee
  • Kausthubham Neethukrishna
  • Gandham S. Bhavani
  • Anju Shukla
  • Sheela Nampoothiri
  • Shubha R. Phadke
  • Mi Jung Park
  • Shiro Ikegawa
  • Zheng Wang
  • Eunyoung Jung
  • Myeong-Sok Lee
  • Jong Hoon Park
  • Eun A. Lee
  • Hongtae Kim
  • Kyungjae Myung
  • Woosung Jeon
  • Kyoungyeul Lee
  • Dongsup Kim
  • Ok-Hwa Kim
  • Murim Choi
  • Han-Woong Lee
  • Younghwan Kim
  • Tae-Joon Cho

Colleges, School and Institutes

External organisations

  • Sookymung Women's University
  • Sungkyunkwan University School of Medicine, Seoul 06351
  • Yonsei University, Seoul 03722
  • Seoul National University College of Medicine, Seoul 03080
  • University of Campina, Sao Paulo 13083-887
  • University of Helsinki and Helsinki University Hospital, Helsinki 00290
  • Kasturba Medical College, Karnataka 576104
  • Samsung Medical Center, Seoul 06351
  • Amrita Insitute of Medical Sciences and Research, Kerala 682041
  • Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh 226014
  • Inje University Sanggye Paik Hospital, Seoul 01757
  • RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639
  • Ulsan National Institute of Science and Technology, Ulsan 44919
  • KAIST, Daejeon 34141


SPONASTRIME dysplasia is a rare recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole exome sequencing, we identified biallelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors, and plays critical roles in resistance to replication stress and maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from individuals are complemented by expressing wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of the TONSL in embryonic development and postnatal growth.


Original languageEnglish
Pages (from-to)439-453
JournalAmerican Journal of Human Genetics
Issue number3
Early online date14 Feb 2019
Publication statusPublished - 7 Mar 2019