Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion encoding an abnormally long polyglutamine tract in the huntingtin protein. Much has been learnt since the mutation was identified in 1993. We review the functions of wild-type huntingtin. Mutant huntingtin may cause toxicity via a range of different mechanisms. The primary consequence of the mutation is to confer a toxic gain of function on the mutant protein and this may be modified by certain normal activities that are impaired by the mutation. It is likely that the toxicity of mutant huntingtin is revealed after a series of cleavage events leading to the production of N-terminal huntingtin fragment(s) containing the expanded polyglutamine tract. Although aggregation of the mutant protein is a hallmark of the disease, the role of aggregation is complex and the arguments for protective roles of inclusions are discussed. Mutant huntingtin may mediate some of its toxicity in the nucleus by perturbing specific transcriptional pathways. HD may also inhibit mitochondrial function and proteasome activity. Importantly, not all of the effects of mutant huntingtin may be cell-autonomous, and it is possible that abnormalities in neighbouring neurons and glia may also have an impact on connected cells. It is likely that there is still much to learn about mutant huntingtin toxicity, and important insights have already come and may still come from chemical and genetic screens. Importantly, basic biological studies in HD have led to numerous potential therapeutic strategies.

Neuronal loss and intraneuronal protein aggregates are characteristics of Huntington's disease (HD), which is one of 10 known neurodegenerative disorders caused by an expanded polyglutamine [poly(Q)] tract in the disease protein. N-terminal fragments of mutant huntingtin produce intracellular aggregates and cause toxicity. Several studies have shown that chaperones suppress poly(Q) aggregation and toxicity/cell death, but the mechanisms by which they prevent poly(Q)-mediated cell death remain unclear. In the present study, we identified heat shock protein 27 (HSP27) as a suppressor of poly(Q) mediated cell death, using a cellular model of HD. In contrast to HSP40/70 chaperones, we showed that HSP27 suppressed poly(Q) death without suppressing poly(Q) aggregation. We tested the hypotheses that HSP27 may reduce poly(Q)-mediated cell death either by binding cytochrome c and inhibiting the mitochondrial death pathway or by protecting against reactive oxygen species (ROS). While poly(Q)-induced cell death was reduced by inhibiting cytochrome c (cyt c) release from mitochondria, protection by HSP27 was regulated by its phosphorylation status and was independent of its ability to bind to cyt c. However, we observed that mutant huntingtin caused increased levels of ROS in neuronal and non-neuronal cells. ROS contributed to cell death because both N-acetyl-L-cysteine and glutathione in its reduced form suppressed poly(Q)-mediated cell death. HSP27 decreased ROS in cells expressing mutant huntingtin, suggesting that this chaperone protects cells against oxidative stress. We propose that a poly(Q) mutation can induce ROS that directly contribute to cell death and that HSP27 is an antagonist of this process.