The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype

The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS–FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G4C2 repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington-like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer’s disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G4C2 repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation

The 'chicken and egg' problem of co-evolution of peptides and their cognate receptors: which came first?

As will be evident from the other chapters in this Volume, small peptide molecules regulate a wide variety of biological processes in both vertebrate and invertebrate species. For each bioactive peptide there exists one or more specific membrane-bound receptors, which transduce(s) the signal of peptide binding into a cellular response. The majority of these receptors share a common topology with seven membrane-spanning domains, an extracellular amino terminus and a cytoplasmically located carboxy terminus. Since this class of receptors translates the process of peptide binding into an intracellular response through an interaction with one or more of a family of GTP-binding proteins (G-proteins), they have been named G-protein-coupled receptors (see Probst et al. 1992; Meyerhof et al. 1993). Other types of peptide receptor are known, including those for growth factors, such as epidermal growth factor, which have a single membrane-spanning domain and an intracellular ligand-activated tyrosine kinase domain (see McInnes and Sykes 1997), that for the peptide Phe-Met-Arg-Phe-amide which contains an integral ligand-gated sodium channel (Lingueglia et al. 1995), and the 200-kDa head-activator receptor of hydra which exhibits sequence similarity to members of the low-density lipoprotein receptor family (Hampe et al., this Vol.). The role of the latter may be that of a carrier protein, binding and presenting head-activator, which is a small hydrophobic peptide, to the ‘true’ head-activator receptor