Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity

Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) α1 subunit (GLRA1) [1][2][3] . Genetic heterogeneity has been confirmed in isolated sporadic cases with mutations in other postsynaptic glycinergic proteins including the GlyR β subunit (GLRB) 4 , gephyrin (GPHN) 5 and RhoGEF collybistin (ARHGEF9) 6 . However, many sporadic patients diagnosed with hyperekplexia do not carry mutations in these genes 2-7 . Here we reveal that missense, nonsense and frameshift mutations in the presynaptic glycine transporter 2 (GlyT2) gene (SLC6A5) 8 also cause hyperekplexia. Patients harbouring mutations in SLC6A5 presented with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnoea episodes. GlyT2 mutations result in defective subcellular localisation and/or decreased glycine uptake, with selected mutations affecting predicted glycine and Na + binding sites. Our results demonstrate that SLC6A5 is a major gene for hyperekplexia and define the first neurological disorder linked to mutations in a Na + /Cl − -dependent transporter for a classical fast neurotransmitter. By analogy, we suggest that in other human disorders where Correspondence and requests for materials (subject to a Material Transfer Agreement) should be addressed to R.J.H. (robert.harvey@pharmacy.ac.uk) or M. I.R. (m.i.rees@swansea.ac.uk).. † these authors contributed equally to this work. COMPETING INTERESTS STATEMENT:The authors declare that they have no competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2011 October 31. Glycine transporters (GlyTs) are members of the Na + /Cl − -dependent neurotransmitter transporter superfamily 9,10 , integral membrane proteins that utilise electrochemical gradients to control the concentration of neurotransmitters at central synapses. This superfamily also includes transporters for GABA, biogenic amines (norepinephrine, dopamine, serotonin, proline), betaine, taurine and creatine. GlyTs have dual functions at both inhibitory and excitatory synapses, resulting from the differential localisation of two distinct transporters 9,10 , GlyT1 and GlyT2. GlyT1 is predominantly expressed in glial cells 9,10 , exhibits a 2 Na + /1 Cl − /1 glycine stoichiometry and bi-directional glycine transport 11 . These properties are appropriate for the control of extracellular glycine concentrations in the submicromolar range for modulation of N-methyl-D-aspartate receptors 12 , and also for lowering extracellular glycine levels at inhibitory glycinergic synapses 13,14 . By contrast, GlyT2 is found in glycinergic axons, exhibits a 3 Na + /1 Cl − /1 glycine stoichiometry and does not display reverse uptake 11 , reflecting an essential role for GlyT2 in maintaining a high presynaptic pool of neurotransmitter at glycinergic synapses 15 . Na + /Cl − -dependent tr...

Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.