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Genotypic and phenotypic studies of inherited prion disease

Webb, T.E.F.; (2010) Genotypic and phenotypic studies of inherited prion disease. Doctoral thesis , UCL (University College London).

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Background: Inherited prion diseases (IPD) show remarkable clinical heterogeneity, posing problems for clinicians in making an early diagnosis and raising questions about genetic or environmental modifiers. The P102L prion protein gene (PRNP) mutation, one of the most frequently identified causes of IPD, has been linked to a large English kindred for three decades. A series of further smaller kindreds did not share apparent ancestry with this large kindred, raising the possibility of distant common ancestry of a rare mutation or no ancestry and relatively common novel mutations occurring. Identification of the genetic modifiers of phenotype may have implications for sporadic and variant Creutzfeldt-Jakob disease (sCJD), and neurodegeneration more widely, while novel mutation rates in PRNP inform study of the unknown aetiology of sCJD. IPD, although rare, has unique advantages in terms of looking for genetic modifiers of prion disease. Methods: Genealogical work and microsatellite haplotyping was carried out on cases of IPD P102L. Clinical information on affected patients was collected retrospectively as well as prospectively. Heritability estimates of IPD were produced by comparing parental and offspring phenotypes. The expanded collection of IPD cases with reliable clinical information (composing P102L and other IPD associated mutations), allowed for the testing of candidate genetic modifiers of phenotype. Polymorphisms previously reported to have an impact on prion disease susceptibility or phenotype were tested, along with a panel of candidate polymorphisms selected from a genome-wide association study (GWAS) in vCJD. Findings: Common ancestry between the known large P102L kindred and a number of previously unlinked P102L kindreds was identified. However, a number of apparently unrelated IPD P102L kindreds remain, suggesting that multiple separate mutational events are responsible: PRNP codon 102 may be a mutation ‘hot- spot’. Microsatellite work on other IPD subtypes in the UK and from elsewhere in Europe also finds evidence of the existence of multiple unrelated kindreds. The genotype-phenotype analysis discovered that codon 129 is a modifier of IPD P102L; in that codon 129 homozygosity is associated with an earlier age at clinical onset. Also identified was a possible effect of APOE genotype on IPD. APOE-E4 is associated with a significantly later age at onset in IPD, which has recently been identified in other categories of neurodegenerative disease. Interpretation: Overall, this work provides indirect support for the plausibility of the ‘somatic mutation hypothesis’ of sporadic CJD (sCJD), by suggesting a relatively frequent novel mutation rate in PRNP. The genetic contribution to phenotypic heterogeneity in IPD was estimated. This contribution is significant and may inform the search for genetic modifiers of susceptibility to acquired prion disease. The models established to analyse IPD as a quantitative trait will be used in future prion disease GWAS.

Type: Thesis (Doctoral)
Title: Genotypic and phenotypic studies of inherited prion disease
Language: English
Additional information: Permission for digitisation not received
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/669507
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