한빛사 논문
Hae Ryung Chang1, 19, Sung Yoon Cho2, 19, Jae Hoon Lee3, 19, Eunkyung Lee1, 19, Jieun Seo4, Hye Ran Lee5, Denise P. Cavalcanti6, Outi Makitie7, Helena Valta7, Katta M. Girisha8, Chung Lee9, Kausthubham Neethukrishna8, Gandham S. Bhavani8, Anju Shukla8, Sheela Nampoothiri10, Shubha R. Phadke11, Mi Jung Park12, Shiro Ikegawa13, Zheng Wang13, 14, Martin R. Higgs15, Grant S. Stewart15, Eunyoung Jung1, Myeong-Sok Lee1, Jong Hoon Park1, Eun A. Lee16, Hongtae Kim16, Kyungjae Myung16, Woosung Jeon17, Kyoungyeul Lee17, Dongsup Kim17, Ok-Hwa Kim18, Murim Choi 4, Han-Woong Lee 3, 20, Yonghwan Kim1, 20,*, Tae-Joon Cho5, 20,*
1 Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Republic of Korea
2 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
3 Department of Biochemistry, Yonsei University, Seoul 03722, Republic of Korea
4 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
5 Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
6 Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo 13083-887, Brazil
7 Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland
8 Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
9 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Republic of Korea
10 Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala 682041, India
11 Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
12 Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul 01757, Republic of Korea
13 Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan
14 McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, People’s Republic of China
15 Institute of Cancer and Genomics Sciences, University of Birmingham, Birmingham, West Midlands B15 2TT, UK
16 Center for Genomic Integrity, Institute for Basic Science, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
17 Department of Bio and Brain Engineering, Korean Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
18 Department of Radiology, Woorisoa Children’s Hospital, Seoul 08291, Republic of Korea
19 These authors contributed equally to this work
20 These authors contributed equally to this work
*Corresponding authors
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.
Keywords : SPONASTRIME dysplasia; skeletal dysplasia; TONSL; DNA replication; DNA repair; short stature; rare genetic diseases; whole-exome sequencing
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