Overview

Pathogenicity: Parkinson's Disease Dementia : Unclear Pathogenicity, Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, None, Parkinson's Disease Dementia
Position: (GRCh38/hg38):Chr17:45989975 C>T
Position: (GRCh37/hg19):Chr17:44067341 C>T
dbSNP ID: rs143956882
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCC to TTC
Reference Isoform: Tau Isoform PNS Tau (758 aa)
Genomic Region: Exon 6

Findings

This variant was detected in one out of 188 individuals diagnosed with Parkinson’s disease with dementia and in one out of 376 cognitively healthy people (Schulte et al., 2015). The individual affected by PD with dementia presented first with bradykinesia and later developed rigor and postural instability in addition to dementia. Resting tremor was absent. Information relating to family history was not available. The cognitively healthy individual was from the KORA-Age cohort based in Germany. Limited information is available about this individual, but the cohort is described as Caucasian and cognitively intact at age 65 or older (Schulte et al., 2012).

This variant was also detected in one out of 72 AD cases and in one out of 58 controls, the latter lacking AD neuropathology postmortem. The ages of these two variant carriers were not reported, nor were details regarding their cognitive health (Frigerio et al., 2015).

This variant is excluded from the six major tau isoforms expressed in the human brain, including Tau-F, the tau isoform conventionally used as the reference for naming MAPT mutations. Therefore, the position of this variant (427) is in reference to a longer isoform, PNS-Tau (P10636-1), which is 776 amino acids in length. 

Neuropathology

Unknown. At least one variant carrier lacked AD neuropathology postmortem (Frigerio et al., 2015).

Biological Effect

Unknown. In silico, PolyPhen2 predicted the S427F variant to be probably damaging (Frigerio et al., 2015).

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References

Paper Citations

1. Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, Kurz A, Diehl-Schmid J, Hüll M, Lichtner P, Eckstein G, Zimprich A, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Lorenzo-Betancor O, Pastor P, Peters A, Gieger C, Estivill X, Meitinger T, Kretzschmar HA, Trenkwalder C, Haass C, Winkelmann J. Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
2. Schulte EC, Mollenhauer B, Zimprich A, Bereznai B, Lichtner P, Haubenberger D, Pirker W, Brücke T, Molnar MJ, Peters A, Gieger C, Trenkwalder C, Winkelmann J. Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease. Neurogenetics. 2012 Aug;13(3):281-5. Epub 2012 Jun 16 PubMed.

Other Citations

1. Frigerio et al., 2015

Further Reading

No Available Further Reading