Characterisation of genotype-phenotype relationships in ALS associated with hexanucleotide repeat expansion of C9orf72

The papers selected represent characterisation of amyotrophic lateral sclerosis (ALS) patients belonging to the C9orf72 genetic variant. The general introduction describes ALS more broadly, both clinically and pathologically, including a summary of proposed molecular mechanisms of pathogenesis. It goes on to discuss the discovery that GGGGCC-repeat expansions of C9orf72 represent the most common genetic variant of this disease.
The first group of papers in section 3 relate to clinical and pathological characterisation of the C9orf72 genetic variant. This includes genetic screening of cohorts of patients suffering from ALS, frontotemporal dementia (FTD), multiple sclerosis and parkinsonism.
The second group of papers in section 4 describes the use of transcriptome analysis, biochemical techniques and immunohistochemistry to study pathogenic mechanisms in C9orf72-ALS. Characterisation of the interactions and behaviour of RNA foci derived from the C9orf72 repeat expansion suggest that these foci sequester proteins important to mRNA splicing. Novel methodology was then used to describe an increase in the splicing error rate in lymphoblastoid cell lines derived from C9orf72-ALS patients, which correlates with disease severity.
The final group of papers in section 5 describes the study of genetic modifiers of the C9orf72-disease phenotype. This includes the development and use of a Southern blotting protocol to size the expansion. This led to some interesting suggestions: that patients with intermediate length, but reputedly pathogenic, expansions do not exhibit haploinsufficiency or typical C9orf72-neuropathology. Finally contribution was made to a larger study of the interaction between TMEM106B genotype and C9orf72-disease.