Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

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dc.contributor University of Helsinki, Lastentautien yksikkö en
dc.contributor University of Helsinki, Children's Hospital en
dc.contributor.author Chang, Hae Ryung
dc.contributor.author Cho, Sung Yoon
dc.contributor.author Lee, Jae Hoon
dc.contributor.author Lee, Eunkyung
dc.contributor.author Seo, Jieun
dc.contributor.author Lee, Hye Ran
dc.contributor.author Cavalcanti, Denise P.
dc.contributor.author Mäkitie, Outi
dc.contributor.author Valta, Helena
dc.contributor.author Girisha, Katta M.
dc.contributor.author Lee, Chung
dc.contributor.author Neethukrishna, Kausthubham
dc.contributor.author Bhavani, Gandham S.
dc.contributor.author Shukla, Anju
dc.contributor.author Nampoothiri, Sheela
dc.contributor.author Phadkei, Shubha R.
dc.contributor.author Park, Mi Jung
dc.contributor.author Ikegawa, Shiro
dc.contributor.author Wang, Zheng
dc.contributor.author Higgs, Martin R.
dc.contributor.author Stewart, Grant S.
dc.contributor.author Jung, Eunyoung
dc.contributor.author Lee, Myeong-Sok
dc.contributor.author Park, Jong Hoon
dc.contributor.author Lee, Eun A.
dc.contributor.author Kim, Hongtae
dc.contributor.author Myung, Kyungjae
dc.contributor.author Jeon, Woosung
dc.contributor.author Lee, Kyoungyeul
dc.contributor.author Kim, Dongsup
dc.contributor.author Kim, Ok-Hwa
dc.contributor.author Choi, Murim
dc.contributor.author Lee, Han-Woong
dc.contributor.author Kim, Yonghwan
dc.contributor.author Cho, Tae-Joon
dc.date.accessioned 2019-11-20T14:22:02Z
dc.date.available 2019-11-20T14:22:02Z
dc.date.issued 2019-03-07
dc.identifier.citation 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 , Phadkei , S R , Park , M J , Ikegawa , S , Wang , Z , Higgs , M R , Stewart , G S , Jung , E , Lee , M-S , Park , J H , Lee , E A , Kim , H , Myung , K , Jeon , W , Lee , K , Kim , D , Kim , O-H , Choi , M , Lee , H-W , Kim , Y & Cho , T-J 2019 , ' Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia ' , American Journal of Human Genetics , vol. 104 , no. 3 , pp. 439-453 . https://doi.org/10.1016/j.ajhg.2019.01.009 en
dc.identifier.issn 0002-9297
dc.identifier.other PURE: 123523967
dc.identifier.other PURE UUID: 37c48188-cb34-41f2-a482-ac1040a17351
dc.identifier.other WOS: 000460541200010
dc.identifier.other Scopus: 85062406571
dc.identifier.uri http://hdl.handle.net/10138/307125
dc.description.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. en
dc.format.extent 15
dc.language.iso eng
dc.relation.ispartof American Journal of Human Genetics
dc.rights en
dc.subject MMS22L-NFKBIL2 COMPLEX en
dc.subject MMS22L-TONSL COMPLEX en
dc.subject DNA-REPLICATION en
dc.subject REPAIR en
dc.subject STRESS en
dc.subject GENE en
dc.subject 1184 Genetics, developmental biology, physiology en
dc.subject 3111 Biomedicine en
dc.title Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia en
dc.type Article
dc.description.version Peer reviewed
dc.description.version Peer reviewed
dc.identifier.doi https://doi.org/10.1016/j.ajhg.2019.01.009
dc.type.uri info:eu-repo/semantics/other
dc.type.uri info:eu-repo/semantics/acceptedVersion
dc.type.uri info:eu-repo/semantics/publishedVersion
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