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Variant types and sites in a single gene could influence the age of onset, severity, and pattern of affected organs of the genetic disease, such as in Marfan syndrome (MFS)-causing FBN1 , and understanding the genotype-phenotype relationship could aid in determining the treatment strategy. In contrast, completely distinct system and/or organ diseases induced by 1 gene mutation have been rarely reported. Transforming growth factor-β (TGF-β) type I receptor-encoding TGFBR1 is such a gene, causing Loeys-Dietz syndrome (LDS) closely related to MFS, and also multiple self-healing squamous epithelioma (MSSE) without clinical overlap. The detailed mechanisms underlying this effect, however, remain elusive. We recently reported the significance of 2 distinct intronic variants (c.973+1G&gt;A and c.806-2A&gt;C) of TGFBR1 , which were both predicted to mediate in-frame exon 5 skipping but caused LDS and MSSE, respectively. On ex vivo minigene splicing assay analysis we demonstrated that 2 different cryptic splice sites were activated, and in-frame and out-of-frame transcripts were produced in LDS and MSSE, respectively, supporting the previously proposed but not yet approved mechanism that loss-of-function and haploinsufficiency-causing variants in serine/threonine kinase domains induce LDS and MSSE, respectively. In this review, we briefly summarize the recent findings and unresolved problems for the pathogenesis of LDS, including the TGF-β signaling paradox: most variants have been verified or predicted to be loss of function in vitro, but these variants enhanced TGF-β signaling in vivo.

circulation reports

Unique Mechanism by Which &lt;i&gt;TGFBR1&lt;/i&gt; Variants Cause 2 Distinct System Diseases ― Loeys-Dietz Syndrome and Multiple Self-Healing Squamous Epithelioma ―