Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46018710 C>T
Position: (GRCh37/hg19):Chr17:44096076 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCT to TCT
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This mutation was identified in an Italian individual with apparently sporadic early onset frontotemporal dementia. At the age of 47 he developed memory loss and mood changes, followed by apathy, disinhibition, and behavioral changes. He did not have a family history of dementia. His father died from lung cancer at the age of 75 and his 76-year-old mother was alive and cognitively healthy at the time of the report. Dementia was also notably absent in five pateral aunts and uncles and in six maternal aunts and uncles. The proband was a mutation carrier, but his unaffected mother and brother were not (Rossi et al., 2012).

The MAPT P364S mutation was subsequently detected in two sisters with a clinical syndrome on the FTD spectrum. In their 50s, both developed cognitive decline, depression, bradykinesia, rigidity, and a forward-bent gait. One was noted to have frequent falls and the other to have symptoms of motor neuron disease, including fasiculations and muscle atrophy. Both died of respiratory insufficiency within a few years of onset. Their mother reportedly had also developed a forward-bent gait and died with dementia at the age of 48 (Popović et al., 2014).

Neuropathology

The neuropathology in the Italian individual is unknown, but MRI showed asymmetrical cerebral atrophy with ventricular enlargement and scattered white-matter lesions (Rossi et al., 2012). Detailed neuropathological analysis was reported for the two sisters, and indicated lesions consistent with tauopathy. Neuronal loss and reactive gliosis were prominent in the nucleus basalis of Meynert, substantia nigra, locus coeruleus, motor cortex, and the anterior horn of the spinal cord. Neuronal tau inclusions were prominent in many brain regions. Globose neurofibrillary tangles were the most abundant type, with some flame-shaped neurofibrillary tangles as well, the latter mostly restricted to the hippocampus. Some Pick body-like inclusions were seen in one case (Popović et al., 2014).

Biological Effect

In vitro, mutant tau exhibited reduced ability to promote microtubule assembly compared with wild-type tau and an increased rate of tau aggregation (Rossi et al., 2012). In addition, increased chromosomal instability and copy-number variations have been reported in lymphocytes and fibroblasts of mutation carriers (Rossi et al., 2013).

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References

Paper Citations

1. Rossi G, Bastone A, Piccoli E, Mazzoleni G, Morbin M, Uggetti A, Giaccone G, Sperber S, Beeg M, Salmona M, Tagliavini F. New mutations in MAPT gene causing frontotemporal lobar degeneration: biochemical and structural characterization. Neurobiol Aging. 2012 Apr;33(4):834.e1-6. Epub 2011 Sep 22 PubMed.
2. Popović M, Fabjan A, Mraz J, Magdič J, Glavač D, Zupan A, Novak MD, Bresjanac M. Tau protein mutation P364S in two sisters: clinical course and neuropathology with emphasis on new, composite neuronal tau inclusions. Acta Neuropathol. 2014 Jul;128(1):155-7. Epub 2014 May 13 PubMed.
3. Rossi G, Conconi D, Panzeri E, Redaelli S, Piccoli E, Paoletta L, Dalprà L, Tagliavini F. Mutations in MAPT gene cause chromosome instability and introduce copy number variations widely in the genome. J Alzheimers Dis. 2013;33(4):969-82. PubMed.

Further Reading

No Available Further Reading