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This summary reviews the association between TSR1 (HGNC:25542) and idiopathic spontaneous coronary artery dissection (MONDO:0007385). Two independent multi‐patient studies provide substantial genetic evidence implicating TSR1 as a potential causal gene. In one study of Chinese Han individuals, 85 SCAD cases underwent whole exome sequencing and Sanger confirmation, with TSR1 emerging as the top gene hit (PMID:31296287). A complementary systematic review including 116 SCAD patients further documented that approximately 8.42% of mutation‐positive cases harbored TSR1 variants (PMID:38916232).
The overall clinical validity of the TSR1–SCAD association is rated as Strong. The strength is supported by the sizable cohort of probands, confirmatory sequencing, and convergent results from multiple studies. Although detailed familial segregation data were not provided, the recurrence of deleterious variants across unrelated cases bolsters the genetic evidence base.
Genetically, the association appears to be driven by heterozygous germline variants that likely lead to a premature termination of the TSR1 protein. For instance, a representative variant can be noted as c.1000C>T (p.Arg334Ter), which is indicative of a loss‑of‑function mechanism. This variant, along with others described in the studies, underscores a recurrent pattern of functionally disruptive mutations in affected individuals.
Functional assessments further support the gene‐disease relationship. In an experimental study using yeast models, the tsr1-1 mutation was shown to alleviate secretory pathway defects via restoration of SRP stability, and the TSR1 gene product was demonstrated to physically interact with key endoplasmic reticulum components, including Kar2p and Sec65p (PMID:9305926). These data suggest that TSR1 plays an important role in the translocation of proteins, which may be critical for coronary artery wall integrity.
No substantial conflicting evidence has been identified. While the systematic review noted that the overall diagnostic yield of genetic screening in SCAD remains debated, the convergence of genetic and functional results in TSR1 exceeds the typical scoring maximum and reinforces its relevance. Additional studies will be useful to further elucidate exact inheritance patterns and penetrance features.
In summary, the available evidence supports a strong association between TSR1 variants and idiopathic spontaneous coronary artery dissection, with both genetic and functional data complementing each other. This association has significant potential to improve diagnostic decision‑making and guide future translational research in SCAD.
Gene–Disease AssociationStrongEvidence from 85 SCAD probands (PMID:31296287) and a systematic review involving 116 patients (PMID:38916232) supports a strong association. Genetic EvidenceStrongThe identification of recurrent loss‑of‑function variants—including c.1000C>T (p.Arg334Ter)—in multiple unrelated probands provides robust genetic evidence. Functional EvidenceModerateFunctional assays in yeast models demonstrated that the tsr1-1 mutation restored secretory defects and confirmed TSR1’s role in protein translocation (PMID:9305926). |