2. Academic Validation
  3. Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

  • Am J Hum Genet. 2019 Mar 7;104(3):439-453. doi: 10.1016/j.ajhg.2019.01.009.
Hae Ryung Chang 1,  Sung Yoon Cho 2,  Jae Hoon Lee 3,  Eunkyung Lee 1,  Jieun Seo 4,  Hye Ran Lee 5,  Denise P Cavalcanti 6,  Outi Mäkitie 7,  Helena Valta 7,  Katta M Girisha 8,  Chung Lee 9,  Kausthubham Neethukrishna 8,  Gandham S Bhavani 8,  Anju Shukla 8,  Sheela Nampoothiri 10,  Shubha R Phadke 11,  Mi Jung Park 12,  Shiro Ikegawa 13,  Zheng Wang 14,  Martin R Higgs 15,  Grant S Stewart 15,  Eunyoung Jung 1,  Myeong-Sok Lee 1,  Jong Hoon Park 1,  Eun A Lee 16,  Hongtae Kim 16,  Kyungjae Myung 16,  Woosung Jeon 17,  Kyoungyeul Lee 17,  Dongsup Kim 17,  Ok-Hwa Kim 18,  Murim Choi 4,  Han-Woong Lee 3,  Yonghwan Kim 19,  Tae-Joon Cho 20
Affiliations

Affiliations

  • 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, São 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 Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan; 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 Department of Biological Sciences, Sookmyung Women's University, Seoul 04310, Republic of Korea. Electronic address: yhkim@sookmyung.ac.kr.
  • 20 Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: tjcho@snu.ac.kr.
PMID: 30773278 DOI: 10.1016/j.ajhg.2019.01.009
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

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

Figures