Clinical & molecular genetics of frontotemporal dementia

Frontotemporal Dementia (FTD) is a heterogeneous group of disorders, characterised byprogressive degeneration of the frontal/temporal lobes. Up to 30% of people with FTDhave an autosomal dominant family history. Among those with the strongest familyhistories, over 80% have mutations in one of three FTD-causing genes. In this thesis, fivenew FTD families and a singleton with very early onset FTD were described. These formedthe basis of further genetic and molecular studies. The body of work began afteridentification of the first FTD-causing gene, microtubule-associated protein Tau (MAPT).By measuring gene expression in cerebellar samples, the MAPT H1 haplotype was found tobe associated with increased Tau expression in vivo. Based on the commonvariant/common disease paradigm, association between the MAPT haplotype andParkinson Disease was explored. This led to the key insight that MAPT and GlycogenSynthase Kinase-3B (GSK3B) haplotypes can interact qualitatively in disease association.This was replicated in an Alzheimer Disease genetic association study. Modelingdemonstrated how qualitative gene-gene interaction may explain some of the heterogeneityand type II error in genetic association studies. The role of MAPT/GSK3B interaction wasfurther explored in a Multiple Sclerosis association study and a lithium pharmacogeneticstudy. The second part of this body of work concerned progranulin (GRN), the secondFTD-causing gene. A nonsense GRN mutation (Q300X), found in a new FTD family, wasshown to have reduced expression in a cell culture model. This was consistent withhaploinsufficiency observed in other GRN mutations. The third part of this body of workwas based on a consanguineous family with FTD/Motor Neuron Disease (MND).Positional cloning was carried out using SNP mapping chips and homozygosity mapping.Several loci were identified but no mutations were detected. Subsequently, a member in thenext generation developed MND, suggesting dominant inheritance. The family was foundhave a repeat expansion in the recently characterized FTD/MND-causing gene C9ORF72.In summary, this thesis highlighted the complex phenotypes and genetics of FTD, andsuggested an approach to genetic testing in FTD. Methodological aspects of geneticassociation studies were also discussed, in light of qualitative gene-gene interactions