SMAD3 – Aneurysm-Osteoarthritis Syndrome (Loeys-Dietz Syndrome Type 3)

SMAD3 encodes a receptor-regulated SMAD protein integral to TGF-β signal transduction in connective tissues. Heterozygous pathogenic variants in SMAD3 cause autosomal dominant aneurysm-osteoarthritis syndrome (Loeys-Dietz syndrome type 3), characterized by aggressive arterial aneurysms and early-onset osteoarthritis with relatively variable systemic connective tissue features. Detailed vascular surveillance and timely surgical intervention are critical once the molecular diagnosis is established.

Genetic evidence includes six unrelated probands with SMAD3 variants (six families) ([PMID:26409702]; [PMID:28185953]; [PMID:29444731]; [PMID:31096651]; [PMID:32022471]; [PMID:35874167]) exhibiting autosomal dominant inheritance. Segregation analysis in two families identified four additional affected relatives harboring the familial SMAD3 variants ([PMID:28185953]; [PMID:32022471]).

The variant spectrum comprises five distinct missense substitutions (p.Arg74Trp, p.Gly245Arg, p.Arg287Trp, p.Arg386Thr, p.Ile67Ser) and one frameshift deletion c.455delC (p.Pro152HisfsTer34). These mutations localize to the MH2 domain or linker regions, disrupting SMAD3 phosphorylation and partner interactions. No recurrent or founder alleles have been reported to date.

Clinically, aneurysm-osteoarthritis syndrome presents with thoracic and abdominal aortic aneurysms or dissections, arterial tortuosity, and striae or mild skeletal findings; early-onset osteoarthritis is variably penetrant. Standardized management includes regular imaging of the entire arterial tree and orthopedic evaluation for joint disease.

Functional studies demonstrate that loss-of-function SMAD3 variants (e.g., p.Ile67Ser) reduce C-terminal phosphorylation, impair nuclear translocation, and diminish transcriptional activation of TGF-β target genes, while patient fibroblasts show decreased SMAD3 stability and increased osteoclastogenic differentiation ([PMID:35874167]). These data support a haploinsufficiency mechanism.

Overall, strong genetic and moderate functional evidence corroborate SMAD3 as the causal gene for aneurysm-osteoarthritis syndrome. SMAD3 testing enables accurate diagnosis, guides vascular surveillance, informs family screening, and underpins future therapeutic strategies targeting TGF-β signaling.

References

• European journal of vascular and endovascular surgery • 2015 • Clinical Exome Sequencing as a Novel Tool for Diagnosing Loeys-Dietz Syndrome Type 3. PMID:26409702
• European journal of medical genetics • 2017 • A novel SMAD3 mutation caused multiple aneurysms in a patient without osteoarthritis symptoms. PMID:28185953
• Cardiology in the Young • 2018 • Isolated aortic dilation without osteoarthritis: a case of SMAD3 mutation. PMID:29444731
• Medicina (Kaunas, Lithuania) • 2019 • Genomic Observations of a Rare/Pathogenic SMAD3 Variant in Loeys–Dietz Syndrome 3 Confirmed by Protein Informatics and Structural Investigation. PMID:31096651
• Molecular genetics & genomic medicine • 2020 • Novel SMAD3 p.Arg386Thr genetic variant co-segregating with thoracic aortic aneurysm and dissection. PMID:32022471
• Bone reports • 2022 • SMAD3 mutation in LDS3 causes bone fragility by impairing the TGF-β pathway and enhancing osteoclastogenesis. PMID:35874167

Evidence Based Scoring (AI generated)