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

Abstract

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>A and c.806-2A>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.

Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes

“…TGFBR1 is a highly conserved gene with a pLI of 0.85, and the identified variant is absent in gnomAD, 1000 genomes and ExAc. Although TGFBR1 missense variants are typically associated with connective tissue disease, splice site and nonsense variants have been reported, and a haploinsufficient mouse model has severe vascular malformations (Fujiwara et al, 2018; Fujiwara et al, 2019; Renard et al, 2014). Loss‐of‐function is an established mechanism for TGFBR1 ‐spectrum disease (MacFarlane et al, 2019).…”

Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections

“…Patients with Loeys–Dietz syndrome (LDS) are characterized by mutations in genes encoding for TGF-β receptors 1 and 2 [ 214 ]. In patients with LDS, increased secretion of TGF-β ligands activates TGFBR1/TGFBR2 complexes and enhances TGF-β signaling [ 60 ]. In vitro, VSMC explants from patients with heterozygous mutations in TGFBR2 showed decreased expression of VSMC contractile proteins and displayed a synthetic VSMC phenotype [ 85 ].…”

Association of TGF-β Canonical Signaling-Related Core Genes With Aortic Aneurysms and Aortic Dissections

“…Heterozygous mutations in the TGFΒR1 gene have been shown to cause multiple self-healing squamous epithelioma (MSSE). Most mutations in MSSE are extracellular ligand-binding domains or truncation mutations of the kinase domain, whereas most mutations in LDS are missense ( Goudie et al, 2011 ; Fujiwara et al, 2019 ).…”