Genetic identification and functional characterisation of novel genes implicated in cerebellar ataxia

The inherited cerebellar ataxias are a group of heterogenous, neurogenerative disorders that affect the cerebellum and other connected regions. The aim of this project is to explore rare neurological diseases that feature cerebellar ataxia from a genetic and functional prospective.
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a pure idiopathic late-onset cerebellar ataxia with a triad of symptoms that include bilateral vestibulopathy, somatosensory deficit and cerebellar impairment. So far there is no genetic basis for CANVAS, despite previous attempts. This project identified a polymorphic (AAAGG)n expansion repeat in the intronic region of RFC1 that is present in 63% of sporadic cases tested, including sibships. We aim to characterise the frequency of the carrier allelic frequency in a normal screening cohort and a late-onset ataxia cohort, estimating expansion size of the pathogenic (AAGGG)n as well as two other polymorphic conformations; (AAAAG)n and (AAAGG)n and SNP haplotype screening all healthy and late-onset ataxia samples to compare with patient haplotype. We also aim to explore the prevalence of the RFC1 repeat expansion in other disease cohorts that share similar clinical characteristics including Multiple systems atrophy (MSA) and Atypical Parkinsonism. Capitalising on the wealth of data contained within 100k Genome Project and Genomics England (GEL) and collaborating with Illumina and their software Expansion Hunter, we hope to develop a way to accurately detect the RFC1 repeat expansion in samples.
Finally, ACBD5 is a peroxisomal membrane protein which are organelles with key roles in metabolic pathways. ACBD5 has been previously implicated in a patient with progressive leukodystrophy, ataxia and retinal dystrophy. Two patients from the same family suffer from autosomal recessive ataxia with severe pure ataxic symptoms including dysarthria, impaired voluntary movement, slow eye movement and mild cognitive impairment. A recessive nonsense mutation in ACBD5 was found using WES in both patients, and through a number of worldwide collaborations we have identified several other families with this mutation. Within this project, we aim to conduct genetic analysis and functional testing to elucidate the pathogenic mechanism of this mutation.