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; 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

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 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. HiggsGrant 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 journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	439-453
Number of pages	15
Journal	American Journal of Human Genetics
Volume	104
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2019.01.009
Publication status	Published - 2019 Mar 7

Bibliographical note

Funding Information:
We are grateful to the affected individuals, their families, and the clinicians for their invaluable contribution. We thank the Smogorzewska Lab, Rockefeller University, New York, New York, USA for reagents; Dr. Je Hoon Jeong for providing the genomic DNA for individual P07; and Thatiane Y. Kanazawa for contributing to the fibroblast culture of individual P04. This research was supported by the Genome Technology to Business Translation Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning ( NRF-2014M3C9A2064684 to T.J.C. and NRF-2014M3C9A2064688 to Y.K.); by an NRF grant funded by the Korean government ( NRF-2017R1A2B4003147 to Y.K.; NRF-2016R1A5A1011974 to Y.K. and M.S.L.; 2017R1A4A1015328 to H.W.L.; and 2015R1A2A1A01003845 to H.W.L.); by Samsung Medical Center ( #GFO2170061 to S.Y.C.); partly by the Department of Science and Technology, India , for the project “Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development” ( SB/SO/HS/005/2014 to K.M.G.); by the Academy of Finland ( No. 318137 to O.M.); by KAKENHI (Grants-in-Aid for Scientific Research) ( No.17K16710 to Z.W.); by the Japan Agency For Medical Research and Development (AMED: No. JP 17ek0109280 to S.I.); by the National Key Research and Development Program of China ; by RIKEN-MOST China ( 2016YFE0128400 to S.I. and Z.W.); by the São Paulo Research Foundation (FAPESP) ( #2015/22145-6 to D.P.C.); and by the Centre for Molecular Medicine at the Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS) (Grant number 63/8/2010-BMS to S.R.P.). Dr. Outi Mäkitie has an affiliation with Folkhälsan Institute of Genetics, Helsinki, Finland.

Funding Information:
We are grateful to the affected individuals, their families, and the clinicians for their invaluable contribution. We thank the Smogorzewska Lab, Rockefeller University, New York, New York, USA for reagents; Dr. Je Hoon Jeong for providing the genomic DNA for individual P07; and Thatiane Y. Kanazawa for contributing to the fibroblast culture of individual P04. This research was supported by the Genome Technology to Business Translation Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2014M3C9A2064684 to T.J.C. and NRF-2014M3C9A2064688 to Y.K.); by an NRF grant funded by the Korean government (NRF-2017R1A2B4003147 to Y.K.; NRF-2016R1A5A1011974 to Y.K. and M.S.L.; 2017R1A4A1015328 to H.W.L.; and 2015R1A2A1A01003845 to H.W.L.); by Samsung Medical Center (#GFO2170061 to S.Y.C.); partly by the Department of Science and Technology, India, for the project “Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development” (SB/SO/HS/005/2014 to K.M.G.); by the Academy of Finland (No.318137 to O.M.); by KAKENHI (Grants-in-Aid for Scientific Research) (No.17K16710 to Z.W.); by the Japan Agency For Medical Research and Development (AMED: No.JP17ek0109280 to S.I.); by the National Key Research and Development Program of China; by RIKEN-MOST China (2016YFE0128400 to S.I. and Z.W.); by the São Paulo Research Foundation (FAPESP) (#2015/22145-6 to D.P.C.); and by the Centre for Molecular Medicine at the Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS) (Grant number 63/8/2010-BMS to S.R.P.). Dr. Outi Mäkitie has an affiliation with Folkhälsan Institute of Genetics, Helsinki, Finland.

Publisher Copyright:
© 2019 American Society of Human Genetics

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Genetics
Genetics(clinical)

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10.1016/j.ajhg.2019.01.009

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Chang, H. R., Cho, S. Y., Lee, J. H., Lee, E., Seo, 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. https://doi.org/10.1016/j.ajhg.2019.01.009

@article{432ed13fc04b436ebfdb6ddfd2f71a85,

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 (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}",

note = "Funding Information: We are grateful to the affected individuals, their families, and the clinicians for their invaluable contribution. We thank the Smogorzewska Lab, Rockefeller University, New York, New York, USA for reagents; Dr. Je Hoon Jeong for providing the genomic DNA for individual P07; and Thatiane Y. Kanazawa for contributing to the fibroblast culture of individual P04. This research was supported by the Genome Technology to Business Translation Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning ( NRF-2014M3C9A2064684 to T.J.C. and NRF-2014M3C9A2064688 to Y.K.); by an NRF grant funded by the Korean government ( NRF-2017R1A2B4003147 to Y.K.; NRF-2016R1A5A1011974 to Y.K. and M.S.L.; 2017R1A4A1015328 to H.W.L.; and 2015R1A2A1A01003845 to H.W.L.); by Samsung Medical Center ( #GFO2170061 to S.Y.C.); partly by the Department of Science and Technology, India , for the project “Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development” ( SB/SO/HS/005/2014 to K.M.G.); by the Academy of Finland ( No. 318137 to O.M.); by KAKENHI (Grants-in-Aid for Scientific Research) ( No.17K16710 to Z.W.); by the Japan Agency For Medical Research and Development (AMED: No. JP 17ek0109280 to S.I.); by the National Key Research and Development Program of China ; by RIKEN-MOST China ( 2016YFE0128400 to S.I. and Z.W.); by the S{\~a}o Paulo Research Foundation (FAPESP) ( #2015/22145-6 to D.P.C.); and by the Centre for Molecular Medicine at the Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS) (Grant number 63/8/2010-BMS to S.R.P.). Dr. Outi M{\"a}kitie has an affiliation with Folkh{\"a}lsan Institute of Genetics, Helsinki, Finland. Funding Information: We are grateful to the affected individuals, their families, and the clinicians for their invaluable contribution. We thank the Smogorzewska Lab, Rockefeller University, New York, New York, USA for reagents; Dr. Je Hoon Jeong for providing the genomic DNA for individual P07; and Thatiane Y. Kanazawa for contributing to the fibroblast culture of individual P04. This research was supported by the Genome Technology to Business Translation Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2014M3C9A2064684 to T.J.C. and NRF-2014M3C9A2064688 to Y.K.); by an NRF grant funded by the Korean government (NRF-2017R1A2B4003147 to Y.K.; NRF-2016R1A5A1011974 to Y.K. and M.S.L.; 2017R1A4A1015328 to H.W.L.; and 2015R1A2A1A01003845 to H.W.L.); by Samsung Medical Center (#GFO2170061 to S.Y.C.); partly by the Department of Science and Technology, India, for the project “Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development” (SB/SO/HS/005/2014 to K.M.G.); by the Academy of Finland (No.318137 to O.M.); by KAKENHI (Grants-in-Aid for Scientific Research) (No.17K16710 to Z.W.); by the Japan Agency For Medical Research and Development (AMED: No.JP17ek0109280 to S.I.); by the National Key Research and Development Program of China; by RIKEN-MOST China (2016YFE0128400 to S.I. and Z.W.); by the S{\~a}o Paulo Research Foundation (FAPESP) (#2015/22145-6 to D.P.C.); and by the Centre for Molecular Medicine at the Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS) (Grant number 63/8/2010-BMS to S.R.P.). Dr. Outi M{\"a}kitie has an affiliation with Folkh{\"a}lsan Institute of Genetics, Helsinki, Finland. Publisher Copyright: {\textcopyright} 2019 American Society of Human Genetics",

year = "2019",

month = mar,

day = "7",

doi = "10.1016/j.ajhg.2019.01.009",

language = "English",

volume = "104",

pages = "439--453",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "3",

}

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

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

N1 - Funding Information: We are grateful to the affected individuals, their families, and the clinicians for their invaluable contribution. We thank the Smogorzewska Lab, Rockefeller University, New York, New York, USA for reagents; Dr. Je Hoon Jeong for providing the genomic DNA for individual P07; and Thatiane Y. Kanazawa for contributing to the fibroblast culture of individual P04. This research was supported by the Genome Technology to Business Translation Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning ( NRF-2014M3C9A2064684 to T.J.C. and NRF-2014M3C9A2064688 to Y.K.); by an NRF grant funded by the Korean government ( NRF-2017R1A2B4003147 to Y.K.; NRF-2016R1A5A1011974 to Y.K. and M.S.L.; 2017R1A4A1015328 to H.W.L.; and 2015R1A2A1A01003845 to H.W.L.); by Samsung Medical Center ( #GFO2170061 to S.Y.C.); partly by the Department of Science and Technology, India , for the project “Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development” ( SB/SO/HS/005/2014 to K.M.G.); by the Academy of Finland ( No. 318137 to O.M.); by KAKENHI (Grants-in-Aid for Scientific Research) ( No.17K16710 to Z.W.); by the Japan Agency For Medical Research and Development (AMED: No. JP 17ek0109280 to S.I.); by the National Key Research and Development Program of China ; by RIKEN-MOST China ( 2016YFE0128400 to S.I. and Z.W.); by the São Paulo Research Foundation (FAPESP) ( #2015/22145-6 to D.P.C.); and by the Centre for Molecular Medicine at the Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS) (Grant number 63/8/2010-BMS to S.R.P.). Dr. Outi Mäkitie has an affiliation with Folkhälsan Institute of Genetics, Helsinki, Finland. Funding Information: We are grateful to the affected individuals, their families, and the clinicians for their invaluable contribution. We thank the Smogorzewska Lab, Rockefeller University, New York, New York, USA for reagents; Dr. Je Hoon Jeong for providing the genomic DNA for individual P07; and Thatiane Y. Kanazawa for contributing to the fibroblast culture of individual P04. This research was supported by the Genome Technology to Business Translation Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2014M3C9A2064684 to T.J.C. and NRF-2014M3C9A2064688 to Y.K.); by an NRF grant funded by the Korean government (NRF-2017R1A2B4003147 to Y.K.; NRF-2016R1A5A1011974 to Y.K. and M.S.L.; 2017R1A4A1015328 to H.W.L.; and 2015R1A2A1A01003845 to H.W.L.); by Samsung Medical Center (#GFO2170061 to S.Y.C.); partly by the Department of Science and Technology, India, for the project “Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development” (SB/SO/HS/005/2014 to K.M.G.); by the Academy of Finland (No.318137 to O.M.); by KAKENHI (Grants-in-Aid for Scientific Research) (No.17K16710 to Z.W.); by the Japan Agency For Medical Research and Development (AMED: No.JP17ek0109280 to S.I.); by the National Key Research and Development Program of China; by RIKEN-MOST China (2016YFE0128400 to S.I. and Z.W.); by the São Paulo Research Foundation (FAPESP) (#2015/22145-6 to D.P.C.); and by the Centre for Molecular Medicine at the Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS) (Grant number 63/8/2010-BMS to S.R.P.). Dr. Outi Mäkitie has an affiliation with Folkhälsan Institute of Genetics, Helsinki, Finland. Publisher Copyright: © 2019 American Society of Human Genetics

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

M3 - Article

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AN - SCOPUS:85062406571

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

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