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Title: Susceptibility genes and phenotype modifiers in prion diseases
Author: Lukic, A.
ISNI:       0000 0004 8498 3365
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Prion diseases show remarkable clinical and neuropathological heterogeneity. All reported cases with definite variant Creutzfeldt-Jakob disease (vCJD) were homozygous at PRNP codon 129. Heterozygosity at codon 219 has been shown to be protective against sporadic CJD (sCJD). Copy number variants (CNVs) are a novel source of genetic variability associated with susceptibility to neuropsychiatric disorders. Aims: Hypotheses tested: · The clinico-pathological phenotype of prion disease is modified by investigation findings, co-deposition of amyloid beta, tau proteins and/or candidate genetic variation. · The MRC Scale can be used for analysis of disease progression in CJD · Copy number variation alters the risk of prion disease in the UK and Papua New Guinea (PNG) Methods: Case reports illustrated genetic susceptibility and phenotypic heterogeneity. The MRC Scale was used to assess disease progression and study power in sCJD. Real-time PCR and gene sequencing were used to assess the role of candidate genes in clinico-pathological heterogeneity. GWAS were used to assess the role of CNVs as susceptibility loci to prion diseases. Results: Two patients with vCJD were heterozygous at codon 219. The MRC scale could be administered daily requiring only 90 patients to provide sufficient study power. Amyloid-β deposition was significantly influenced by APOE ε4 haplotype in definite sCJD. Prion protein and hyperphosphorylated tau deposition were influenced by MAPTH1c haplotype. CNV duplications at chromosome 10 and 14 were significantly enriched in cases when compared to controls. The finding was confirmed using real-time PCR but was not replicated in the German cohort. Analysis using Penn CNV revealed a nominally significant association of CNV deletion at PARK2 gene. Conclusion: Heterozygosity at codon 219 is protective against sCJD but may confer susceptibility to vCJD. Patient stratification and assessments using MRC Scale allowed adequate study power to justify future therapeutic trials. MAPTH1c haplotype played a role in both prion and tau protein deposition. Chromosome 10 and 14 duplications and deletion at PARK2 gene may play a role in prion disease susceptibility.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available