Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

Hae Ryung Chang, Sung Yoon Cho, Jae Hoon Lee, Eunkyung Lee, Jieun Seo, 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 R. Higgs & 15 others Grant S. 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, Yonghwan Kim, Tae Joon Cho

Research output: Contribution to journalArticle

Abstract

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 (WES), we identified bi-allelic 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 which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of 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 (KI) 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 TONSL in embryonic development and postnatal growth.

Original languageEnglish
Pages (from-to)439-453
Number of pages15
JournalAmerican Journal of Human Genetics
Volume104
Issue number3
DOIs
Publication statusPublished - 07-03-2019

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Exome
DNA Replication
DNA Repair
Computer Simulation
Embryonic Development
Virulence
Spine
Fibroblasts
Maintenance
Genome
Bone and Bones
Skin
Mutation
Growth
In Vitro Techniques
Protein Domains

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Chang, H. R., Cho, S. Y., Lee, J. H., Lee, E., Seo, J., Lee, H. R., ... Cho, T. J. (2019). Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia. American Journal of Human Genetics, 104(3), 439-453. https://doi.org/10.1016/j.ajhg.2019.01.009
Chang, Hae Ryung ; Cho, Sung Yoon ; Lee, Jae Hoon ; Lee, Eunkyung ; Seo, Jieun ; Lee, Hye Ran ; Cavalcanti, Denise P. ; Mäkitie, Outi ; Valta, Helena ; Girisha, Katta M. ; Lee, Chung ; Neethukrishna, Kausthubham ; Bhavani, Gandham S. ; Shukla, Anju ; Nampoothiri, Sheela ; Phadke, Shubha R. ; Park, Mi Jung ; Ikegawa, Shiro ; Wang, Zheng ; Higgs, Martin R. ; Stewart, Grant S. ; Jung, Eunyoung ; Lee, Myeong Sok ; Park, Jong Hoon ; Lee, Eun A. ; Kim, Hongtae ; Myung, Kyungjae ; Jeon, Woosung ; Lee, Kyoungyeul ; Kim, Dongsup ; Kim, Ok Hwa ; Choi, Murim ; Lee, Han Woong ; Kim, Yonghwan ; Cho, Tae Joon. / Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 3. pp. 439-453.
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abstract = "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 (WES), we identified bi-allelic 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 which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of 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 (KI) 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 TONSL in embryonic development and postnatal growth.",
author = "Chang, {Hae Ryung} and Cho, {Sung Yoon} and Lee, {Jae Hoon} and Eunkyung Lee and Jieun Seo and Lee, {Hye Ran} and Cavalcanti, {Denise P.} and Outi M{\"a}kitie and Helena Valta and Girisha, {Katta M.} and Chung Lee and Kausthubham Neethukrishna and Bhavani, {Gandham S.} and Anju Shukla and Sheela Nampoothiri and Phadke, {Shubha R.} and Park, {Mi Jung} and Shiro Ikegawa and Zheng Wang and Higgs, {Martin R.} and Stewart, {Grant S.} and Eunyoung Jung and Lee, {Myeong Sok} and Park, {Jong Hoon} and Lee, {Eun A.} and Hongtae Kim and Kyungjae Myung and Woosung Jeon and Kyoungyeul Lee and Dongsup Kim and Kim, {Ok Hwa} and Murim Choi and Lee, {Han Woong} and Yonghwan Kim and Cho, {Tae Joon}",
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Chang, HR, Cho, SY, Lee, JH, Lee, E, Seo, J, Lee, HR, Cavalcanti, DP, Mäkitie, O, Valta, H, Girisha, KM, Lee, C, Neethukrishna, K, Bhavani, GS, Shukla, A, Nampoothiri, S, Phadke, SR, Park, MJ, Ikegawa, S, Wang, Z, Higgs, MR, Stewart, GS, Jung, E, Lee, MS, Park, JH, Lee, EA, Kim, H, Myung, K, Jeon, W, Lee, K, Kim, D, Kim, OH, Choi, M, Lee, HW, Kim, Y & Cho, TJ 2019, 'Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia', American Journal of Human Genetics, vol. 104, no. 3, pp. 439-453. https://doi.org/10.1016/j.ajhg.2019.01.009

Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia. / Chang, Hae Ryung; Cho, Sung Yoon; Lee, Jae Hoon; Lee, Eunkyung; Seo, Jieun; Lee, Hye Ran; Cavalcanti, Denise P.; Mäkitie, Outi; Valta, Helena; Girisha, Katta M.; Lee, Chung; Neethukrishna, Kausthubham; Bhavani, Gandham S.; Shukla, Anju; Nampoothiri, Sheela; Phadke, Shubha R.; Park, Mi Jung; Ikegawa, Shiro; Wang, Zheng; Higgs, Martin R.; Stewart, Grant S.; Jung, Eunyoung; Lee, Myeong Sok; Park, Jong Hoon; Lee, Eun A.; Kim, Hongtae; Myung, Kyungjae; Jeon, Woosung; Lee, Kyoungyeul; Kim, Dongsup; Kim, Ok Hwa; Choi, Murim; Lee, Han Woong; Kim, Yonghwan; Cho, Tae Joon.

In: American Journal of Human Genetics, Vol. 104, No. 3, 07.03.2019, p. 439-453.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

AU - Chang, Hae Ryung

AU - Cho, Sung Yoon

AU - Lee, Jae Hoon

AU - Lee, Eunkyung

AU - Seo, Jieun

AU - Lee, Hye Ran

AU - Cavalcanti, Denise P.

AU - Mäkitie, Outi

AU - Valta, Helena

AU - Girisha, Katta M.

AU - Lee, Chung

AU - Neethukrishna, Kausthubham

AU - Bhavani, Gandham S.

AU - Shukla, Anju

AU - Nampoothiri, Sheela

AU - Phadke, Shubha R.

AU - Park, Mi Jung

AU - Ikegawa, Shiro

AU - Wang, Zheng

AU - Higgs, Martin R.

AU - Stewart, Grant S.

AU - Jung, Eunyoung

AU - Lee, Myeong Sok

AU - Park, Jong Hoon

AU - Lee, Eun A.

AU - Kim, Hongtae

AU - Myung, Kyungjae

AU - Jeon, Woosung

AU - Lee, Kyoungyeul

AU - Kim, Dongsup

AU - Kim, Ok Hwa

AU - Choi, Murim

AU - Lee, Han Woong

AU - Kim, Yonghwan

AU - Cho, Tae Joon

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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 (WES), we identified bi-allelic 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 which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of 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 (KI) 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 TONSL in embryonic development and postnatal growth.

AB - 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 (WES), we identified bi-allelic 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 which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of 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 (KI) 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 TONSL in embryonic development and postnatal growth.

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U2 - 10.1016/j.ajhg.2019.01.009

DO - 10.1016/j.ajhg.2019.01.009

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JO - American Journal of Human Genetics

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