Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

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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 , Phadkei , S R , Park , M J , Ikegawa , S , Wang , Z , Higgs , M R , Stewart , G S , Jung , E , Lee , M-S , Park , J H , Lee , E A , 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

Title: Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia
Author: 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; Phadkei, 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
Contributor organization: Lastentautien yksikkö
Children's Hospital
University of Helsinki
HUS Children and Adolescents
Date: 2019-03-07
Language: eng
Number of pages: 15
Belongs to series: American Journal of Human Genetics
ISSN: 0002-9297
DOI: https://doi.org/10.1016/j.ajhg.2019.01.009
URI: http://hdl.handle.net/10138/307125
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 as-says 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.
1184 Genetics, developmental biology, physiology
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: acceptedVersion

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