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유전체 항상성 연구단
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Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

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Title
Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia
Author(s)
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.; Phadke S.R.; Park M.J.; Ikegawa S.; Wang Z.; Higgs M.R.; Stewart G.S.; Jung E.; Lee M.-S.; Park J.H.; Eun A. Lee; Hongtae Kim; Kyungjae Myung; Jeon W.; Lee K.; Kim D.; Kim O.-H.; Choi M.; Lee H.-W.; Kim Y.; Cho T.-J.
Publication Date
2019-03
Journal
AMERICAN JOURNAL OF HUMAN GENETICS, v.104, no.3, pp.439 - 453
Publisher
CELL PRESS
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. © 2019 American Society of Human Genetic
URI
https://pr.ibs.re.kr/handle/8788114/5875
ISSN
0002-9297
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > Journal Papers (저널논문)
Files in This Item:
Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia. The American Journal of Human Genetics 104, 1–15, March 7, 2019.pdfDownload

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