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.
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We are grateful to the affected individuals, their families, and the clinicians for their invaluable contribution. We thank the Smogorzewska Lab, Rockefeller University, New York, New York, USA for reagents; Dr. Je Hoon Jeong for providing the genomic DNA for individual P07; and Thatiane Y. Kanazawa for contributing to the fibroblast culture of individual P04. This research was supported by the Genome Technology to Business Translation Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning ( NRF-2014M3C9A2064684 to T.J.C. and NRF-2014M3C9A2064688 to Y.K.); by an NRF grant funded by the Korean government ( NRF-2017R1A2B4003147 to Y.K.; NRF-2016R1A5A1011974 to Y.K. and M.S.L.; 2017R1A4A1015328 to H.W.L.; and 2015R1A2A1A01003845 to H.W.L.); by Samsung Medical Center ( #GFO2170061 to S.Y.C.); partly by the Department of Science and Technology, India , for the project “Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development” ( SB/SO/HS/005/2014 to K.M.G.); by the Academy of Finland ( No. 318137 to O.M.); by KAKENHI (Grants-in-Aid for Scientific Research) ( No.17K16710 to Z.W.); by the Japan Agency For Medical Research and Development (AMED: No. JP 17ek0109280 to S.I.); by the National Key Research and Development Program of China ; by RIKEN-MOST China ( 2016YFE0128400 to S.I. and Z.W.); by the São Paulo Research Foundation (FAPESP) ( #2015/22145-6 to D.P.C.); and by the Centre for Molecular Medicine at the Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS) (Grant number 63/8/2010-BMS to S.R.P.). Dr. Outi Mäkitie has an affiliation with Folkhälsan Institute of Genetics, Helsinki, Finland.
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