Mutations

APP G709S

Overview

Pathogenicity: Parkinson's Disease Dementia : Not Classified
Clinical Phenotype: Parkinson's Disease Dementia
Position: (GRCh38/hg38):Chr21:25891808 G>A
Position: (GRCh37/hg19):Chr21:27264120 G>A
dbSNP ID: rs201269325
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGT to AGT
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This variant was detected in one out of 188 individuals with Parkinson’s disease with dementia (Schulte et al., 2015). This individual presented with resting tremor, and also developed bradykinesia, rigor, postural instability, and dementia. An uncle also had PD. The variant was absent in 188 PD cases without dementia and 376 controls.

This variant was found in the gnomAD variant database at a frequency of 0.00004245 with an allele count of 12 (v2.1.1, Oct 2021). All carriers were heterozygotes, most with either European or Asian ancestry.

Neuropathology

Unknown.

Biological Effect

The biological effect of this mutation is unknown, but in vitro experiments using the C99 APP fragment indicate G709 forms part of a di-glycine hinge whose flexibility appears to be important for γ-secretase cleavage (Götz et al., 2019). Moreover, the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

Also of note, the amino acid lies within a cholesterol-binding site as determined by NMR resonance spectroscopy and site-directed mutagenesis (Barrett et al., 2012). 

Last Updated: 19 Oct 2021

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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. Götz A, Mylonas N, Högel P, Silber M, Heinel H, Menig S, Vogel A, Feyrer H, Huster D, Luy B, Langosch D, Scharnagl C, Muhle-Goll C, Kamp F, Steiner H. Modulating Hinge Flexibility in the APP Transmembrane Domain Alters γ-Secretase Cleavage. Biophys J. 2019 Jun 4;116(11):2103-2120. Epub 2019 May 3 PubMed.
  3. Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR. The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science. 2012 Jun 1;336(6085):1168-71. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  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.

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