Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

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Chang, Hae Ryung ^[1] ; Cho, Sung Yoon ^[2] ; Lee, Jae Hoon ^[3] ; Lee, Eunkyung ^[1] ; Seo, Jieun ^[4] ; Lee, Hye Ran ^[5] ; Cavalcanti, Denise P. ^[6] ; Makitie, Outi ^{[7, 8]} ; Valta, Helena ^{[7, 8]} ; Girisha, Katta M. ^[9] ; Lee, Chung ^[10] ; Neethukrishna, Kausthubham ^[9] ; Bhavani, Gandham S. ^[9] ; Shukla, Anju ^[9] ; Nampoothiri, Sheela ^[11] ; Phadkei, Shubha R. ^[12] ; Park, Mi Jung ^[13] ; Ikegawa, Shiro ^[14] ; Wang, Zheng ^{[14, 15, 16, 17]} ; Higgs, Martin R. ^[18] ; Stewart, Grant S. ^[18] ; Jung, Eunyoung ^[1] ; Lee, Myeong-Sok ^[1] ; Park, Jong Hoon ^[1] ; Lee, Eun A. ^[19] ; Kim, Hongtae ^[19] ; Myung, Kyungjae ^[19] ; Jeon, Woosung ^[20] ; Lee, Kyoungyeul ^[20] ; Kim, Dongsup ^[20] ; Kim, Ok-Hwa ^[21] ; Choi, Murim ^[4] ; Lee, Han-Woong ^[3] ; Kim, Yonghwan ^[1] ; Cho, Tae-Joon ^[5]

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^[1] Sookmyung Womens Univ, Dept Biol Sci, Seoul 04310 - South Korea

^[2] Sungkyunkwan Univ, Samsung Med Ctr, Dept Pediat, Sch Med, Seoul 06351 - South Korea

^[3] Yonsei Univ, Dept Biochem, Seoul 03722 - South Korea

^[4] Seoul Natl Univ, Dept Biomed Sci, Coll Med, Seoul 03080 - South Korea

^[5] Seoul Natl Univ, Dept Orthopaed Surg, Coll Med, Seoul 03080 - South Korea

^[6] Univ Estadual Campinas, Fac Med Sci, Dept Med Genet, BR-13083887 Campinas, SP - Brazil

^[7] Univ Helsinki, Childrens Hosp, FIN-00290 Helsinki - Finland

^[8] Helsinki Univ Hosp, Helsinki 00290 - Finland

^[9] Manipal Acad Higher Educ, Kasturba Med Coll, Dept Med Genet, Manipal 576104, Karnataka - India

^[10] Samsung Med Ctr, Samsung Genome Inst, Seoul 06351 - South Korea

^[11] Amrita Inst Med Sci & Res Ctr, Dept Pediat Genet, Cochin 682041, Kerala - India

^[12] Sanjay Gandhi Postgrad Inst Med Sci, Dept Med Genet, Lucknow 226014, Uttar Pradesh - India

^[13] Inje Univ, Dept Pediat, Sanggye Paik Hosp, Seoul 01757 - South Korea

^[14] RIKEN Ctr Integrat Med Sci, Lab Bone & Joint Dis, Tokyo 1088639 - Japan

^[15] Chinese Acad Med Sci, McKusick Zhang Ctr Genet Med, Beijing 100005 - Peoples R China

^[16] Chinese Acad Med Sci, State Key Lab Med Mol Biol, Inst Basic Med Sci, Beijing 100005 - Peoples R China

^[17] Peking Union Med Coll, Beijing 100005 - Peoples R China

^[18] Univ Birmingham, Inst Canc & Genom Sci, Birmingham B15 2TT, W Midlands - England

^[19] Ulsan Natl Inst Sci & Technol, Inst Basic Sci, Ctr Genom Integr, Ulsan 44919 - South Korea

^[20] Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Daejeon 34141 - South Korea

^[21] Woorisoa Childrens Hosp, Dept Radiol, Seoul 08291 - South Korea

• Tipo de documento: Artigo Científico
• Fonte: American Journal of Human Genetics; v. 104, n. 3, p. 439-453, MAR 7 2019.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 15/22145-6 - Contribuição ao estudo clínico-etiológico das displasias esqueléticas e disostoses no Brasil
• Beneficiário: Denise Pontes Cavalcanti
• Modalidade de apoio: Auxílio à Pesquisa - Regular