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 Higgs; Grant 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

doi:10.1016/j.ajhg.2019.01.009

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

Cancer and Genomic Sciences

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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, 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 language	English
Pages (from-to)	439-453
Journal	American Journal of Human Genetics
Volume	104
Issue number	3
Early online date	14 Feb 2019
DOIs	https://doi.org/10.1016/j.ajhg.2019.01.009
Publication status	Published - 7 Mar 2019

Keywords

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

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2019.01.009Licence: None: All rights reserved

Revised Manuscript_AJHG-D-18-00536 20190103
Checked for eligibility: 30/04/2019 Chang, Hae Ryung, et al. "Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia." The American Journal of Human Genetics 104.3 (2019): 439-453. https://www.sciencedirect.com/journal/the-american-journal-of-human-genetics https://doi.org/10.1016/j.ajhg.2019.01.009
Accepted author manuscript, 545 KBLicence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

7 Citations
1 Article

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.
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198 Downloads (Pure)

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Chang, H. R., Cho, S. Y., Lee, J. H., Lee, E., Soo, J., Lee, H. R., Cavalcanti, D. P., Mäkitie, O., Valta, H., Girisha, K. M., Lee, C., Neethukrishna, K., Bhavani, G. S., Shukla, A., Nampoothiri, S., Phadke, S. R., Park, M. J., Ikegawa, S., Wang, Z., ... Cho, T-J. (2019). Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia. American Journal of Human Genetics, 104(3), 439-453. Advance online publication. https://doi.org/10.1016/j.ajhg.2019.01.009

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title = "Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia",

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, 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.",

keywords = "DNA repair, DNA replication, SPONASTRIME dysplasia, TONSL, rare genetic diseases, short stature, skeletal dysplasia, whole-exome sequencing",

author = "Chang, {Hae Ryung} and Cho, {Sung Yoon} and Lee, {Jae Hoon} and Eunkyung Lee and Jieun Soo 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 Martin Higgs and Grant Stewart and Eunyoung Jung and Myeong-Sok Lee and Park, {Jong Hoon} and Lee, {Eun A.} and Hongtae Kim and Kyungjae Myung and Woosung Jeon and Kyoungyeul Lee and Dongsup Kim and Ok-Hwa Kim and Murim Choi and Han-Woong Lee and Younghwan Kim and Tae-Joon Cho",

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Chang, HR, Cho, SY, Lee, JH, Lee, E, Soo, 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, M , Stewart, G, Jung, E, Lee, M-S, Park, JH, Lee, EA, Kim, H, Myung, K, Jeon, W, Lee, K, Kim, D, Kim, O-H, Choi, M, Lee, H-W, Kim, Y & Cho, T-J 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

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T1 - Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

AU - Chang, Hae Ryung

AU - Cho, Sung Yoon

AU - Lee, Jae Hoon

AU - Lee, Eunkyung

AU - Soo, 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

AU - Stewart, Grant

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, Younghwan

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, 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.

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, 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.

KW - DNA repair

KW - DNA replication

KW - SPONASTRIME dysplasia

KW - TONSL

KW - rare genetic diseases

KW - short stature

KW - skeletal dysplasia

KW - whole-exome sequencing

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U2 - 10.1016/j.ajhg.2019.01.009

DO - 10.1016/j.ajhg.2019.01.009

M3 - Article

SN - 0002-9297

VL - 104

SP - 439

EP - 453

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

Abstract

Keywords

ASJC Scopus subject areas

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Research output

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

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