Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonus, Parkinsonism
Position: (GRCh38/hg38):Chr21:25891784 G>T
Position: (GRCh37/hg19):Chr21:27264096 G>T
dbSNP ID: rs63750264
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to TTC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17
Research Models: 13

Findings

This mutation was originally found in three generations of a family of Romanian origin by a research group at Indiana University School of Medicine. The average age of onset was 45.7 years (Murrell et al., 1991). It was later found in an Austrian individual (known as P. 31) of Romanian ancestry with a disease onset of approximately 38 years, as well as in two German siblings (known as P.32 and P.65) with onset at 40 and 37 years, respectively (Finckh et al., 2005).

The variant was also reported in a Hungarian family with AD (Zádori et al., 2017). The proband was a woman whose age at onset was 40 years old and her symptoms included severe short-term memory loss and language impairment, epileptic seizures, myoclonus-like jerks, and hypokinesis. Several members of her family, including her elder sister, mother, an aunt, and an uncle developed similar symptoms and died between the ages of 48 and 65. Of note, the ages at onset in the mother’s generation (early 50s) were older than those of the proband and her sister (early 40s). In addition to the proband, four additional carriers of the mutation were identified, but they were all under the expected age at onset (31 years or younger).

This variant was absent from the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology

A female carrier from the original family had severe atrophy of the frontal lobes with enlarged lateral ventricles, and neuronal loss and gliosis throughout the neocortex. She also had abundant, diffuse amyloid plaques and Aβ angiopathy, with neuritic plaques and neurofibrillary tangles in the frontal cortex. In addition, α-synuclein deposits were observed in the amygdala (Yang et al., 2022).

Cryo-electron microscopy revealed that, whereas tau filaments were similar to those from sporadic AD cases with a ratio of paired helical filaments to straight filaments of approximately 4:1 (Falcon et al., 2018), Aβ filaments, forming a core of paired S-shaped protofilaments, were arranged in a pattern distinct from those seen in sporadic AD (Yang et al., 2022; Jan 2022 news). The carrier's Aβ filaments were similar, however, to filaments in the brain of another individual with familial AD (carrying the PSEN1 F105L mutation).

In addition, an MRI brain scan of the Hungarian proband revealed generalized atrophy (Zádori et al., 2017). Although levels of Aβ42 in cerebrospinal fluid were decreased, tau and phospho-tau levels were normal.

Biological Effect

Although the results have varied, studies using cell-based assays or isolated proteins both indicate V717F alters the processing of APP. In cultured cells, the mutation has generally been reported to increase the Aβ42/Aβ40 ratio in conditioned media. COS cells expressing mutant APP695 secreted approximately equal levels of Aβ40 and Aβ42/43. This represented an increase in the Aβ42(43)/Aβ40 ratio, as cells expressing wild-type APP secreted predominantly Aβ40 (Tamaoka et al., 1994). A similar result was reported in M17 human neuroblastoma cells. Compared with cells expressing wild-type APP, cells transfected with APP V717F secreted relatively more Aβ42/43 than Aβ40 (Suzuki et al., 1994). A study focused primarily on the E693G “Arctic” APP mutation showed that HEK293 cells transfected with APP V717F produced an elevated Aβ42/Aβ40 ratio due to both an increase in secreted Aβ42 and a decrease in Aβ40 (Nilsberth et al., 2001).

However, two in vitro studies found that the Aβ42/Aβ40 ratio increase was modest (Bolduc et al., 2016) or non-existent (Devkota et al., 2021, Feb 2021 news). Instead, the latter reported an increase in longer, membrane-anchored Aβ peptides—Aβ48, 46, and 45—, an increase in ε cleavage, and a preference for the Aβ48 → Aβ45 → Aβ42 → Aβ38 pathway over the Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway. This variant may stall the γ-secretase-substrate complex and the presence of the membrane-anchored complex per se may be toxic (Devkota et al., 2024; Nov 2023 news).

A cryo-electron microscopy study of an APP fragment bound to PSEN1 revealed that V717 is nestled in a shallow hydrophobic pocket formed by PSEN1 F237, I387, and F388 (Zhou et al., 2019; Jan 2019 news).

Also, altered production of the β-CTF fragment, produced by BACE cleavage of APP, may be an important source of toxicity. Neurons derived from induced pluripotent stem cells carrying the mutation were deficient at endocytosing and sorting APP and lipoproteins, disrupting their transport to axons (Woodruff et al., 2016, Oct 2016 news). Inhibiting BACE rescued the defect suggesting that β-CTF, which has been reported to suppress endocytosis, was to blame.

A transcriptomic analysis of SH-SY5Y neuroblastoma cells expressing this variant revealed multiple alterations compared with cells expressing wildtype APP (Petralia et al., 2022).

V717F's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. V717F: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. V717F: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Research Models

Several rodent models carrying this mutation, as well as human iPSC lines derived from patient carriers, have been created. Furthermore, neuronal cell models have been generated directly from adult fibroblasts (Sun et al., 2023, Jun 2023 news). Unlike neurons differentiated from induced pluripotent stem cells, these transdifferentiated neurons, called tNeurons, retained epigenetic marks of aging.

Last Updated: 14 Feb 2024

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References

News Citations

Mutations Citations

Paper Citations

Sun Z, Kwon J-S, Ren Y, Chen S, Cates K, Lu X, Walker CK, Karahan H, Sviben S, Fitzpatrick JA, Valdez C, Houlden H, Karch CM, Bateman RJ, Sato C, Mennerick SJ, Diamond MI, Kim J, Tanzi RE, Holtzman DM, Yoo AS. Endogenous recapitulation of Alzheimers disease neuropathology through human 3D direct neuronal reprogramming. 2023 May 25 10.1101/2023.05.24.542155 (version 1) bioRxiv.
Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science. 1991 Oct 4;254(5028):97-9. PubMed.
Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
Zádori D, Füvesi J, Timár E, Horváth E, Bencsik R, Szépfalusi N, Must A, Vécsei L, Molnár MJ, Klivényi P. The Report of p.Val717Phe Mutation in the APP Gene in a Hungarian Family With Alzheimer Disease: A Phenomenological Study. Alzheimer Dis Assoc Disord. 2017;31(4):343-345. PubMed.
Yang Y, Arseni D, Zhang W, Huang M, Lövestam S, Schweighauser M, Kotecha A, Murzin AG, Peak-Chew SY, Macdonald J, Lavenir I, Garringer HJ, Gelpi E, Newell KL, Kovacs GG, Vidal R, Ghetti B, Ryskeldi-Falcon B, Scheres SH, Goedert M. Cryo-EM structures of amyloid-β 42 filaments from human brains. Science. 2022 Jan 14;375(6577):167-172. Epub 2022 Jan 13 PubMed.
Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ, Ghetti B, Scheres SH, Goedert M. Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold. Acta Neuropathol. 2018 Nov;136(5):699-708. Epub 2018 Oct 1 PubMed.
Tamaoka A, Odaka A, Ishibashi Y, Usami M, Sahara N, Suzuki N, Nukina N, Mizusawa H, Shoji S, Kanazawa I. APP717 missense mutation affects the ratio of amyloid beta protein species (A beta 1-42/43 and a beta 1-40) in familial Alzheimer's disease brain. J Biol Chem. 1994 Dec 30;269(52):32721-4. PubMed.
Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L, Eckman C, Golde TE, Younkin SG. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science. 1994 May 27;264(5163):1336-40. PubMed.
Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Näslund J, Lannfelt L. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.
Bolduc DM, Montagna DR, Seghers MC, Wolfe MS, Selkoe DJ. The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase. Elife. 2016 Aug 31;5 PubMed.
Devkota S, Williams TD, Wolfe MS. Familial Alzheimer's disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of ≥45 residues. J Biol Chem. 2021;296:100281. Epub 2021 Jan 12 PubMed.
Devkota S, Zhou R, Nagarajan V, Maesako M, Do H, Noorani A, Overmeyer C, Bhattarai S, Douglas JT, Saraf A, Miao Y, Ackley BD, Shi Y, Wolfe MS. Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. Cell Rep. 2024 Feb 27;43(2):113761. Epub 2024 Feb 13 PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Woodruff G, Reyna SM, Dunlap M, Van Der Kant R, Callender JA, Young JE, Roberts EA, Goldstein LS. Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations. Cell Rep. 2016 Oct 11;17(3):759-773. PubMed.
Petralia MC, Mangano K, Quattropani MC, Lenzo V, Nicoletti F, Fagone P. Computational Analysis of Pathogenetic Pathways in Alzheimer's Disease and Prediction of Potential Therapeutic Drugs. Brain Sci. 2022 Jun 24;12(7) PubMed.

Mutations

APP V717F (Indiana)

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