Distinct variants affecting differential splicing of TGFBR1 exon 5 cause either Loeys–Dietz syndrome or multiple self-healing squamous epithelioma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-04-30

AUTHORS

Takayuki Fujiwara, Norifumi Takeda, Hironori Hara, Hiroyuki Morita, Jun Kishihara, Ryo Inuzuka, Hiroki Yagi, Sonoko Maemura, Haruhiro Toko, Mutsuo Harada, Yuichi Ikeda, Hidetoshi Kumagai, Seitaro Nomura, Eiki Takimoto, Hiroshi Akazawa, Junya Ako, Issei Komuro

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. More... »

PAGES

1151-1158

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41431-018-0127-1

DOI

http://dx.doi.org/10.1038/s41431-018-0127-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1103678136

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29706644


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