The AAGGG Repeat Expansion in the RFC1 gene: Investigating the functional consequences

Nucleotide repeat expansions are frequent causes of neurodegeneration but little is known about the mechanisms leading to neuronal degeneration. We recently identified a biallelic intronic AAGGG nucleotide repeat expansion in the replication-factor-C subunit-1 (RFC1) as a common cause of ataxia (Cortese-et-al, Nature Genetics, April2019). RFC1 is known to play a key role in DNA damage recognition and recruitment of DNA repair enzymes and AAGGG expansion is not loss-of-function. The objective of the project is to investigate the 100,000 genomes resource for novel neurodegeneration associated expansions and in cell culture models, characterise neurodegeneration caused by RFC1 AAGGG and newly identified expansions.