Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

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, Martin HiggsGrant Stewart, 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

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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


  • DNA repair
  • DNA replication
  • SPONASTRIME dysplasia
  • rare genetic diseases
  • short stature
  • skeletal dysplasia
  • whole-exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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  • Biallelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

    Burrage, L., Reynolds, J., Baratang, N., Phillips, J., Wegner, J., McFarquhar, A., Higgs, M., Christiansen, A., Lanza, D., Seavitt, J., Jain, M., Li, X., Parry, D., Raman, V., Chitayat, D., Chinn, I., Bertuch, A., Karaviti, L., Schlesinger, A., Earl, D., & 39 othersBamshad, M., Savarirayan, R., Doddapaneni, H., Muzny, D., Jhangiani, S., Eng, C., Gibbs, R., Bi, W., Emrick, L., Rosenfeld, J., Postlethwait, J., Westerfield, M., Dickinson, M., Beaudet, A., Ranza, E., Huber, C., Cormier-Daire, V., Shen, W., Mao, R., Heaney, J., Orange, J., Undiagnosed Diseases Network, Bertola, D., Yamamoto, G., Baratela, W., Butler, M., Ali, A., Adeli, M., Cohn, D., Krakow, D., Jackson, A., Lees, M., Offiah, A., Carlston, C., Carey, J., Stewart, G., Bacino, C., Campeau, P. & Lee, B., 7 Mar 2019, In: American Journal of Human Genetics. 104, 3, p. 422-438 17 p.

    Research output: Contribution to journalArticlepeer-review

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    6 Citations (Scopus)
    198 Downloads (Pure)

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