Genetic studies of frontotemporal dementia : with particular emphasis on the tau gene

Frontotemporal dementia (FTD) is next to Alzheimer's disease one of the common causes of early onset progressive dementia. FTD is mainly characterized by personality changes such as disinhibition, although there are large clinical and neuoropathological variations among the cases. The disorder is partly hereditary and three genomic regions have been linked to familial forms of the disease. The work presented in this thesis aimed at identifying genetic factors that directly or indirectly cause FTD, by investigating families with dominant inheritance patterns, as well as clinic-based FTD cases. Particular focus has been directed to the gene for the microtubule associated protein tau, which seems to have a pivotal role in several neurodegenerative disorders known as tauopathies.

In the initial study, linkage analysis was performed to two specified regions on chromosome 3 and 17 in a Swedish family with early-onset rapidly progressive FTD. Linkage was identified to chromosome 17q21 with a maximum two-point LOD score of 2.76 at 0=0 for the marker D17S806. Sequencing of the tau gene localized on chromosome 17q21 failed to identify any mutations segregating with the disease in this family. Many other FTD families with shared clinical and neuropathological features were independently linked to an overlapping region on chromosome 17q21 and the disorder was collectively given the term Fromotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17).

In collaboration with other groups we characterized the FTDP-17 candidate region in order to identify the gene causing the disease. A physical- and transcript map was constructed by assembling a contig of genomic clones and by positioning known genes and EST clusters on this physical map. Nineteen known genes and a number of ESTs were localized to the candidate region. Furthermore, seven novel genes were identified by exon-trapping and isolated in their full-length sequences. A number of genes mapped to the region were investigated for mutations. However, no mutations segregating in the FTDP- 17 families were identified. Hence, we extended the sequencing of the most obvious candidate, the tau gene, to a large number of families and to extended regions of the gene. Three missense mutations, G272V, P301L and R406W, were identified in the regions of tau that associates with microtubules. In addition, three intronic mutations 3' of the exon 10 5' splice site were observed. Other groups independently confirmed these results, as tau missense and 5' splice mutations now are identified as the major cause of FTDP- 17.

The frequency of tau mutations was investigated in a Swedish clinic-based FTD population, although no additional tau mutations were found. Thus, tau mutations were rare among Swedish FTD cases and other genetic and/or environmental components must be operating. Consequently, we aimed at investigating such genetic factors, using two different approaches. Possible defects of the tau gene as larger deletions or alteration of splicing was investigated in a Swedish FTDP-17 family, where no tau mutations previously had been found. However, using methods such as Southern blot and RT-PCR, no pathological changes were observed. Furthermore, we investigated the presence of mutations in six other candidate genes on chromosome 17q2 1: gamma-tubulin, glial fibrillary acid protein (GFAP), human VH- I related dual specificity phosphatase (VHR), rap2-interacting protein 8 (RPIP8), P35, and the recently identified FTDCG1. However, no pathological changes were found in any of the genes. In a second approach, we investigated the apolipoprotein E (APOE) genotype distribution in the clinic-based FTD population. This study showed that the APOE epsilon4 allele was overrepresented among FID cases. Furthermore, cerebrospinal fluid (CSF) levels of the tau protein were measured in this population and found to be significantly increased in a subset of the cases.

In conclusion, the findings of missense and 5' splice mutations in the tau gene in FTDP- 17 families reported by us and other groups, was a major breakthrough in dementia research as it showed that tau can have a pivotal role in neurodegeneration. However, tau mutations are not present in all FTDP- 17 families, and were found to be a rare cause of FTD among clinical cases. Extended investigation of tau and sequencing of other genes resulted in negative findings. Thus, it remains to continue the search for additional causes of FTD to get further insight into the pathogenesis of neurodegeneration. We also conclude that positive results regarding APOE epsilon4 association and increased levels of CSF tau gives further evidence for a common pathogenic pathway in the disease processes for several tauopathies such as AD and FTD, with both tau and APOE being a link between the different disorders.

List of scientific papers

I. Froelich S, Basun H, Forsell C, Lilius L, Axelman K, Andreadis A, Lannfelt L (1997). "Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21" Am J Med Genet 74(4): 380-5
https://pubmed.ncbi.nlm.nih.gov/9259373

II. Froelich S, Houlden H, Rizzu P, Chakraverty S, Baker M, Kwon J, Nowotny P, Isaacs A, Nowotny V, Wauters E, van Baren MJ, Oostra BA, Hardy J, Lannfelt L, Goate A, Hutton M, Lendon CL, Heutink P (1999). "Construction of a detailed physical and transcript map of the FTDP-17 candidate region on chromosome 17q21" Genomics 60(2): 129-36
https://pubmed.ncbi.nlm.nih.gov/10486204

III. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S et al. (1998). "Association of missense and 5-splice-site mutations in tau with the inherited dementia FTDP-17." Nature 393(6686): 702-5
https://pubmed.ncbi.nlm.nih.gov/9641683

IV. Froelich Fabre S, Forsell C, Viitanen M, Sjogren M, Wallin A, Blomberg M, Andersen C, Wahlund LO, Lannfelt L (2001). "Clinic-based cases with frontotemporal dementia show increased cerebrospinal fluid tau, high apolipoprotein E epsilon4 frequency, but no tau gene mutations." Exp Neurol 168: 413-8

V. Froelich Fabre S, Axelman P, Almqvist A, Ingelson M, Spillantini MG, Lannfelt L (2001). "Extended investigation of the tau gene and other candidate genes on chromsome 17q21 in a Swedish FTDP-17 family." (Manuscript)