What is the clinical evidence from this study?

Study design: Other. Population: Loeys-Dietz syndrome. Intervention: tgfbr2b knockdown. Primary outcome: Expression levels of bmpr1 and grem1b.

March 3, 2026

Development of a zebrafish model of Loeys–Dietz syndrome through tgfbr2b knockdown

Key Result

Knockdown of tgfbr2b was utilized to develop a zebrafish model of Loeys-Dietz syndrome, though specific quantitative results were not reported in this supplementary methods section.

Key Points

The zebrafish model showed cardiovascular abnormalities and dysmorphic features, akin to human Loeys-Dietz syndrome.
TGF-β1 expression increased alongside BMP signaling pathway genes, impacting craniofacial structure and cardiac function.
Using morpholino oligonucleotides, tgfbr2b knockdown led to significant developmental issues in zebrafish, aiding in disease understanding for LDS and MFS comparison. This model helps clarify the distinct pathological mechanisms in Loeys-Dietz syndrome compared to Marfan syndrome.

PICO

Population

Loeys-Dietz syndrome

Intervention / Comparator

tgfbr2b knockdown

Primary Outcome

Expression levels of bmpr1 and grem1b

Abstract

Loeys-Dietz syndrome (LDS), an autosomal dominant connective tissue disorder, was initially considered "atypical" Marfan syndrome (MFS). MFS is caused by mutations in FBN1 encoding fibrillin 1, which binds to transforming growth factor β (TGF-β) to inhibit it from binding to TGF-β receptors. In contrast, LDS is caused by mutations in TGF-β-related genes, including TGFBR2. Some clinical symptoms of LDS, including cardiovascular and skeletal complications, are similar to those observed in MFS; however, arterial tortuosity and widespread aortic aneurysm, hypertelorism, and cleft palate or bifida uvula are specific to LDS. Therefore, the role and difference of the TGF-β signaling pathway in LDS remains unclear. To elucidate the pathological mechanisms of LDS and the phenotypical differences between MFS and LDS, an LDS zebrafish model was established by knocking down tgfbr2b using an antisense morpholino oligonucleotide (tgfbr2b morphant), and the phenotype and expression of genes and proteins related to the TGF-β signaling pathway were investigated. tgfbr2b morphants presented with a dysmorphic face, bent body, and cardiovascular abnormalities, some of which were similar to those observed in patients with LDS. The TGF-β1 gene and protein expression, as well as the genes related to the BMP signaling pathway, were upregulated, and the smad1/5/9 protein exhibited enhanced phosphorylation. These results suggest that dysregulation of BMP signaling during development plays an essential role in the craniofacial dysmorphism and cardiac abnormalities observed in the LDS zebrafish model. Our study clarified the differences of pathological mechanism between MFS and LDS.

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