Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response (original) (raw)

Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response. Aicardi-Goutières syndrome (AGS, MIM225750) is a genetically determined encephalopathy whose clinical importance is magnified because it closely mimics (and hence is often misdiagnosed as) the sequelae of congenital infection 1. AGS and congenital virus infection are both associated with an increased production of interferon alpha (IFNα) 2. Furthermore, a disturbance of IFN-α homeostasis is considered central to the pathogenesis of the autoimmune disorder systemic lupus erythematosus (SLE) 3. In keeping with this, some children with AGS also develop an early-onset form of SLE 4-7. These related clinical observations led us to predict in 2003 that elucidation of the genetic basis of AGS would identify cellular components with key roles in the pathogenesis of acquired autoimmune disease 8. In 2006 we reported that recessive mutations in any of the genes encoding the 3′→5′ exonuclease TREX1 (TREX1, previously known as AGS1) 9 or the three nonallelic components of the RNASEH2 endonuclease complex (RNASEH2B, RNASEH2C and RNASEH2A, also known as AGS2, AGS3 and AGS4, respectively) 10 result in AGS. We further showed that heterozygous TREX1 mutations can cause both a dominant form of AGS and a cutaneous subtype of SLE, called familial chilblain lupus (CHBL, MIM610448) 11 .