Henry Houlden & Kenneth Fischbeck Collaboration
Title: Genome wide arrays and next generation sequencing in the analysis of spinocerebellar degeneration.
Patients with movement disorders such as ataxia and parkinsonism have selective neuronal vulnerability that affects certain neurons, and defines the clinical and pathological phenotype. In patients with spinocerebellar degeneration the primary neurons that are affected, and progressively degenerate are in the cerebellum. This condition is inherited in families where only half the genes have been identified. The commonest form of spinocerebellar degeneration occurs without a family history but like other forms of neurodegeneration there is highly likely to be a significant genetic risk combined with environmental factors. We have previously used genome wide arrays to carry out homozygosity mapping and identify structural variants in a number of disorders. We have also recently carried out successful genome wide association studies in Parkinson’s and Alzheimer’s disease. In addition to these powerful genetic techniques we have started to use next generation sequencing to rapidly analyze large genomic regions.
Our laboratories are fully equipped and routinely use state of the art genomic techniques as indicated by our recent genetic findings. In addition, the NINDS laboratory has particular expertise in the functional analysis of disease genes. Dr Fischbeck’s laboratory was the first to identify and characterize the trinucleotide repeat disorder Kennedy’s disease, and they have recently developed a mouse model of this condition. In this project the student will use genome wide arrays to analyze a large number of families with spinocerebellar degeneration where the disease gene is unknown. Where structural variants and linked regions are identified, they will use next generation sequencing to identify the causative variant. They will then analyze the function of the disease genes identified and characterize these pathways in human brain tissue from ataxia patients.