trimeric ribonuclease H2 complex. The catalytic subunit A is in blue (active site in magenta) and the structural subunits B and C are in brown and pink, respectively. Positions highlighted in yellow indicate known sites of AGS mutations. The most common AGS mutation - which replaces an alanine amino acid residue with threonine in subunit B - is shown as a green sphere. AGS is a genetically heterogeneous disease resulting from mutations in any of seven genes encoding: a 3' repair exonuclease with preferential activity on single stranded DNA (TREX1); any of the three components of the ribonuclease H2 endonuclease complex acting on ribonucleotides in RNA:DNA hybrids (RNASEH2A, RNASEH2B, RNASEH2C); a SAM domain and HD domain containing protein which functions as a deoxynucleoside triphosphate triphosphohydrolase (SAMHD1); an enzyme catalysing the hydrolytic deamination of adenosine to inosine in double-stranded RNA (ADAR1); and the cytosolic double-stranded RNA receptor (MDA5, also known as IFIH1). Mutations in the gene OCLN on chromosome 5q13.2, which is thought to cause band-like calcification in the brain, have been discovered in affected individuals and categorized as BLCPMG which often associated with AGS. In most cases, except for IFIH1- and rare cases of TREX1- and ADAR1-related disease, these mutations follow an autosomal recessive inheritance pattern (and thus the parents of an affected child face a 1 in 4 risk of having a further child similarly affected at every conception). AGS can be divided into subtypes based on the gene in which the causative mutation occurs. A survey of 374 patients with an AGS diagnosis reported that the most frequent mutations occurred in RNASEH2B. Type OMIM Gene Locus Frequency AGS1 TREX1 3p21.31 23% (1% dominant) AGS2 RNASEH2B 13q14.3 36% AGS3 RNASEH2C 11q13.1 12% AGS4 RNASEH2A 19p13.2 5% AGS5 SAMHD1 20q11.23 13% AGS6 ADAR 1q21.3 7% (1% dominant) AGS7 IFIH1 2q24 3% (all dominant) AGS-associated mutations have been found to show incomplete penetrance in some cases, with children in the same family with the same mutations showing markedly different neurological and developmental outcomes. Clinical features and disease course vary somewhat by genotype, with TREX1 associated with likely in utero onset and high mortality rate, and RNASEH2B mutations associated with slightly milder neurological impairments, lower interferon activity, and longer lifespan. RNASEH2 is employed in genome surveillance to remove misincorporated ribonucleotides in DNA. In mice, the loss of RNASEH2 activity causes neuroinflammation, atrophy of the cerebellum, and white matter defects that mirror AGS. The signaling of unrepaired DNA damage appears to be the basic cause of the neurodegenerative features that are characteristic of AGS.
Aicardi–Goutières syndrome
Witteveen–Kolk syndrome
Pork–cat syndrome
Woodhouse–Sakati syndrome
RAPADILINO syndrome
Phidippides cardiomyopathy
Bannayan–Riley–Ruvalcaba syndrome
Galloway Mowat syndrome