TGFBR1 – Loeys-Dietz Syndrome 1

Autosomal-dominant variants in TGFBR1 underlie Loeys-Dietz syndrome 1 (LDS1). Heterozygous TGFBR1 mutations have been reported in at least six unrelated LDS1 probands, including de novo nonsense c.1237C>T (p.Arg413Ter) ([PMID:35181021]), recurrent de novo missense c.722C>T (p.Ser241Leu) ([PMID:16596670]), and additional kinase-domain substitutions c.1460G>A (p.Arg487Gln) ([PMID:17652900]) and c.1126A>G (p.Lys376Glu) ([PMID:30701076]).

Segregation analysis in a multigenerational family demonstrated co-segregation of the c.1043G>A (p.Cys348Tyr) variant with disease in an affected sibling (n=1) ([PMID:31475485]).

The TGFBR1 variant spectrum in LDS1 includes nonsense mutations (e.g., c.1237C>T (p.Arg413Ter)), missense substitutions within the serine/threonine kinase domain (e.g., c.688G>A (p.Ala230Thr); c.343+1G>C splice-donor disruption), and frameshift/truncating alleles (c.1342dup (p.Gln448ProfsTer15)) consistent with loss-of-function and dominant-negative effects.

Functional studies show that loss-of-function and dominant-negative TGFBR1 variants impair SMAD2/3 phosphorylation, activate paradoxical TGF-β signaling in patient aortic tissue, and induce contractile defects in hiPSC-derived smooth muscle cells that are rescued by activin A and rapamycin ([PMID:29706644]; [PMID:30701076]; [PMID:34346740]).

Mechanistically, TGFBR1 haploinsufficiency or dominant-negative disruption of the kinase domain perturbs canonical TGF-β signaling, leading to vascular aneurysm, skeletal dysplasia, and characteristic craniofacial features.

Given the variable prenatal and postnatal presentation, including untypical fetal skeletal findings, targeted sequencing of TGFBR1 is essential for definitive LDS1 diagnosis, risk stratification, and guiding aortic surveillance and potential therapeutic interventions.

References

• Taiwanese journal of obstetrics & gynecology • 2022 • A novel nonsense mutation of TGFBR1 in a fetus with untypical Loeys-Dietz syndrome 1. PMID:35181021
• American journal of medical genetics. Part A • 2006 • FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited. PMID:16596670
• Circulation journal • 2007 • Phenotypic heterogeneity of Marfan-like connective tissue disorders associated with mutations in the transforming growth factor-beta receptor genes. PMID:17652900
• Molecular genetics & genomic medicine • 2019 • Pathogenic effect of a TGFBR1 mutation in a family with Loeys-Dietz syndrome. PMID:31475485
• Human genome variation • 2019 • Activation of TGF-β signaling in an aortic aneurysm in a patient with Loeys-Dietz syndrome caused by a novel loss-of-function variant of TGFBR1. PMID:30701076
• Circulation • 2021 • hiPSC Modeling of Lineage-Specific Smooth Muscle Cell Defects Caused by TGFBR1A230T Variant, and Its Therapeutic Implications for Loeys-Dietz Syndrome. PMID:34346740
• European journal of human genetics • 2023 • Truncating variants in the penultimate exon of TGFBR1 escaping nonsense-mediated mRNA decay cause Loeys-Dietz syndrome. PMID:36599937

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