Epidemiology and molecular mechanism of frontotemporal lobar degeneration/amyotrophic lateral sclerosis with repeat expansion mutation in C9orf72.

GGGGCC hexanucleotide repeat expansions in C9orf72 were identified in 2011 as the genetic cause of frontotemporal lobar degeneration (FTLD)/amyotrophic lateral sclerosis (ALS) linked to chromosome 9. Since then, a number of studies have been conducted to delineate the molecular epidemiology of the repeat expansions and the molecular pathophysiology of the disease. The frequency of the repeat expansions considerably varied among countries. The frequency of the repeat expansions was high in European populations and populations of European descent and a substantial proportion of sporadic FTLD or ALS patients also have the mutations in these populations. On the other hand, the frequency was extremely low in Asia or Oceania except for limited regions including Kii Peninsula of Japan. A founder effect seems to strongly influence the regional differences in the frequency, but there is no definitive evidence that supports the notion that the repeat expansions arose in a single founder or multiple founders. As a disease-causing mechanism, several molecular mechanisms have been proposed, including conformational changes of DNA (G-quadruplex formation and hypermethylation) or RNA (G-quadruplex formation) molecules, altered transcriptional levels of C9orf72, sequestration of RNA-binding proteins, bidirectional transcription, formation of RNA foci, and neurotoxicity of dipeptide repeat proteins generated by repeat-associated non-ATG-initiated translation. Further investigations on the molecular mechanisms of neurodegeneration are expected to lead to the development of therapeutic interventions for this disease as well as for other diseases associated with non-coding repeat expansions.