Abstract
Variants in TGFBR1 have been reported to induce two completely distinct diseases, namely Loeys–Dietz syndrome (LDS) and multiple self-healing squamous epithelioma (MSSE). However, detailed mechanisms underlying this effect remain unknown. We report a Japanese familial case of LDS with a novel splice donor site variant in TGFBR1 gene (c.973 + 1 G > A; NG_007461.1). The intronic variant was predicted to mediate in-frame exon 5 skipping within the serine/threonine kinase (STK) domain, which may also be mediated by a similar TGFBR1 variant of a splice acceptor site in intron 4 (c.806-2 A > C), identified in a British familial case of MSSE. Therefore, ex vivo splicing and functional assays were performed in mammalian cells to evaluate the effect of these sequence variants. The MSSE variant activated a cryptic acceptor site at 76 bp downstream of the 3′ natural splice acceptor site, which produced an out-of-frame transcript (r.807_882del, p.Asn270Thrfs*8). In contrast, the LDS variant generated two types of in-frame transcription products, r.[806_973del, 965_973 del], and produced two functionally inactivated proteins, p.[Asp269_Gln324del, Thr323_Gly325del], as a result of exon 5 skipping and the activation of a cryptic donor splice site at 9 bp upstream of the 5′ natural splice donor site, respectively. Our results support the previously proposed but not yet approved mechanism that dominant-negative and truncating variants in STK domain induce LDS and MSSE, respectively.
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Acknowledgements
We would like to thank the patient and her family for their participation in this study. This study was supported by a Grant-in-Aid for Research on Rare and Intractable Diseases from the Japan Agency for Medical Research and Development (N.T.).
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Fujiwara, T., Takeda, N., Hara, H. et al. Distinct variants affecting differential splicing of TGFBR1 exon 5 cause either Loeys–Dietz syndrome or multiple self-healing squamous epithelioma. Eur J Hum Genet 26, 1151–1158 (2018). https://doi.org/10.1038/s41431-018-0127-1
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DOI: https://doi.org/10.1038/s41431-018-0127-1
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