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Type: Artigo
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.
Makitie, 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
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.
Subject: Doenças do desenvolvimento ósseo
Country: Estados Unidos
Editor: Elsevier
Rights: Fechado
Identifier DOI: 10.1016/j.ajhg.2019.01.009
Date Issue: 2019
Appears in Collections:FCM - Artigos e Outros Documentos

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