Aicardi-Goutières Syndrome caused by SAMHD1 mutation: Pathogenesis and Beyond

Aicardi-Goutières Syndrome (AGS) is a rare monogenic autoinflammatory disorder primarily affecting the central nervous system. It is characterized by elevated levels of type I interferon (IFN-I) in the cerebrospinal fluid. Mutations in SAMHD1 gene cause AGS type 5. The primary function of SAMHD1 is to maintain genome stability by regulating the dNTP pool through its enzymatic activity. This review comprehensively describes the role of loss-of-function mutations in SAMHD1 in the pathogenesis of AGS. It covers the molecular structure and function of SAMHD1, as well as its relationship with type I interferon responses. We explore potential mechanisms by which SAMHD1 mutations lead to AGS, including the accumulation of DNA damage, upregulation of LINE-1 reverse transcription, and abnormal RNA metabolism. Additionally, we summarize current research progress, therapeutic challenges, and future directions for AGS. A deeper understanding of SAMHD1 function may lead to new strategies for diagnosing and treating SAMHD1-mutation-associated AGS.