2025-02-27 カリフォルニア大学サンフランシスコ校(UCSF)
<関連情報>
- https://www.ucsf.edu/news/2025/02/429526/1-gene-variant-poised-cure-devastating-inherited-disease
- https://rupress.org/jem/article-abstract/222/4/e20242179/277292/The-common-HAQ-STING-allele-prevents-clinical?redirectedFrom=fulltext
HAQ STING対立遺伝子がCOPA症候群の臨床的浸透を妨げる
The common HAQ STING allele prevents clinical penetrance of COPA syndrome
Christopher S. Law,Brett M. Elicker,Santosh Kurra,Margaret Mei-Kay Wong,Bo Yuan,Alice Grossi,Ronald M. Laxer,Stefano Volpi,Dilan Dissanayake,Tomohiko Taguchi,David B. Beck,Tiphanie P. Vogel,Anthony K. Shum
Journal of Experimental Medicine Published:February 27 2025
DOI:https://doi.org/10.1084/jem.20242179
COPA syndrome, an autosomal-dominant inborn error of immunity, is nonpenetrant in ∼20% of individuals, with no known mediators of protection. Recent studies implicate STING in the pathogenesis of COPA syndrome. We show that the common HAQ STING allele mediates complete clinical protection. We sequenced 35 individuals with COPA mutations, 26 affected patients and 9 unaffected carriers, finding HAQ STING co-segregation with clinical nonpenetrance. Exome sequencing identified only the mutations comprising HAQ STING as variants shared by unaffected carriers and absent in patients. Experimentally, we found that HAQ STING acts dominantly to dampen COPA-dependent STING signaling. Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome. Our study is the first report of a common and well-tolerated allele mediating complete clinical protection from a severe genetic disorder. Our findings redefine the diagnostic criteria for COPA syndrome, expose functional differences among STING alleles with broad scientific and clinical implications, and reveal a potential universal gene therapy approach for patients.
