Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia, Tauopathy consistent with Pick's Disease
Position: (GRCh38/hg38):Chr17:45996657 G>T
Position: (GRCh37/hg19):Chr17:44074023 G>T
dbSNP ID: rs63750376
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to GTC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 9
Research Models: 2

Findings

This mutation was identified in a large Dutch kindred originally described as having hereditary Pick's disease (see pedigree in Groen and Endtz, 1982). The family, known as HFTD2, had at least 34 affected individuals over seven generations. The mean age of onset in the family was 47 years. Presenting symptoms generally included changes in behavior, including disinhibition, aggression, and obsessional behavior (Heutink et al., 1997). Postmortem analysis confirmed the diagnosis of frontotemporal dementia in 15 individuals (Hutton et al., 1998).

Neuropathology

Multiple cases from the HFTD2 kindred have been examined neuropathologically. Severe frontotemporal lobe atrophy was commonly observed, as well as neuronal loss in the hippocampus and caudate nucleus. "Ballooned cells" were observed in the cortex and basal ganglia, as well as tau-positive inclusions in multiple cortical and subcortical areas (Heutink et al., 1997). A neuropathological study of three cases, aged 54, 56, and 57 at time of death, showed severe loss of neurons and gliosis in the frontal and temporal cortex, and to a lesser extent in the parietal cortex. Neuronal loss was also observed in the hippocampus. The caudate nucleus was degenerated and there was a severe loss of pigmented cells in the substantia nigra. In one case, a few Pick bodies were observed (Spillantini et al., 1998).

Biological Effect

This mutation produces tau proteins that are more favorable substrates for phosphorylation by brain protein kinases than wild-type tau isoforms (Alonso et al., 2004).

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References

Paper Citations

1. Groen JJ, Endtz LJ. Hereditary Pick's disease: second re-examination of the large family and discussion of other hereditary cases, with particular reference to electroencephalography, a computerized tomography. Brain. 1982 Sep;105 (Pt 3):443-59. PubMed.
2. Heutink P, Stevens M, Rizzu P, Bakker E, Kros JM, Tibben A, Niermeijer MF, van Duijn CM, Oostra BA, van Swieten JC. Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a genetic and clinicopathological study of three Dutch families. Ann Neurol. 1997 Feb;41(2):150-9. PubMed.
3. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.
4. Spillantini MG, Crowther RA, Kamphorst W, Heutink P, van Swieten JC. Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol. 1998 Nov;153(5):1359-63. PubMed.
5. Alonso Ad, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem. 2004 Aug 13;279(33):34873-81. Epub 2004 Jun 9 PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database