Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891784 G>C
Position: (GRCh37/hg19):Chr21:27264096 G>C
dbSNP ID: rs63750264
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to CTC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This was the fourth AD-associated mutation discovered involving codon 717 in APP. It was first reported in an American family in which the proband was diagnosed with Alzheimer's disease at age 38. Her presentation was typical for her family, with short-term memory problems appearing in the mid- to late 30s and gradual deterioration over approximately 10 years. The mean age of onset in this family was 38 years (range: 35 to 39 years) based on data from four affected family members. While three affected members carried the mutation, five unaffected members who were older than the mean age at onset, did not, indicating cosegregation of the mutation with disease (Murrell et al., 2000).

Another kindred, known as "Family 171," was also found to carry this mutation. This Caucasian family of English ancestry had a later age of onset. The mean age of onset for the seven affected family members was 50 years (range: 48 to 57 years). The mean age at death was 61 years (range: 57 to 68 years). In addition to the progressive memory impairment typical of AD, some members of this family also experienced seizures and hallucinations (Godbolt et al., 2006).

Two additional unrelated patients of German origin were also found to carry this mutation. One patient, identified as P. 43, had dementia onset at age 50 and a family history of dementia. The other, identified as P. 83, had dementia onset at age 43 and a family history of dementia (Finckh et al., 2005).

This mutation was detected in a Japanese family affected by early onset Alzheimer’s disease. The reported pedigree shows nine affected family members over three generations. The average age at onset in this family was 47.1 ± 3.1 years (range: 42 to 52 years). Typical of his family, the proband developed short-term memory loss and concentration deficits at age 45. Other symptoms in this family included psychiatric symptoms (e.g., depression, irritability, emotional lability), seizures, myoclonus, gait disturbance, and pyramidal signs. The mutation was detected in three affected family members, but not in the proband's unaffected mother, indicating the mutation cosegregates with disease. The mutation was also absent from 50 unrelated controls. MRI showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices (Abe et al., 2012).

Additional reports of mutation carriers include two kindreds (Ghetti et al., 2008; Hooli et al., 2012) and an individual Caucasian patient affected by early onset AD (onset at age 59) whose diagnosis was confirmed by autopsy (Sassi et al., 2014).

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

Neuropathology

In at least two carriers, neuropathology was consistent with AD (Hooli et al., 2012). MRIs of affected members of the Japanese family showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices (Abe et al., 2012).

Biological Effect

In primary mouse neurons, this variant, whose Aβ peptides are referred to as V46L, resulted in an increased Aβ42/Aβ40 ratio due to increased levels of Aβ42 and decreased levels of Aβ40 (De Jonghe et al., 2001). A subsequent in vitro study also found a statistically significant increase in the Aβ42/Aβ40 ratio in proteoliposomes, although not in a detergent-solubilized system (Devkota et al., 2021, Feb 2021 news). This latter study also revealed that total Aβ peptide production was increased relative to wild-type APP, with the sum of peptides from the Aβ48 → Aβ45 → Aβ42 → Aβ38 processing pathway being increased, while the sum of peptides from the Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway was decreased. Inefficient processing of longer, membrane-anchored peptides that may be pathogenic was apparent with increases in Aβ48, Aβ46, and Aβ45 levels. Moreover, while successive trimming of Aβ peptides was decreased, ε-cleavage was increased and shifted towards the Aβ48 pathway.

The V717L substitution also appears to interfere with autophagy. The ATG9A protein, which is involved in autophagosome formation, was upregulated in neurons derived from induced pluripotent stem cells from a carrier, yet these cells had low LC3B-II/I ratios suggesting impaired autophagosome formation (Shirotani et al., 2023).

V717L has been predicted to be "possibly damaging" in silico (Sassi et al., 2014), and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, consistent with a deleterious effect (CADD v.1.6, Oct 2021).

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).

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.

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References

News Citations

1. Are the Long Aβ Peptides the Real Bad Guys? 5 Feb 2021
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Murrell JR, Hake AM, Quaid KA, Farlow MR, Ghetti B. Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. Arch Neurol. 2000 Jun;57(6):885-7. PubMed.
2. Godbolt AK, Beck JA, Collinge JC, Cipolotti L, Fox NC, Rossor MN. A second family with familial AD and the V717L APP mutation has a later age at onset. Neurology. 2006 Feb 28;66(4):611-2. PubMed.
3. 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.
4. Abe M, Sonobe N, Fukuhara R, Mori Y, Ochi S, Matsumoto T, Mori T, Tanimukai S, Ueno SI. Phenotypical difference of Amyloid Precursor Protein (APP) V717L mutation in Japanese family. BMC Neurol. 2012 Jun 15;12(1):38. PubMed.
5. Ghetti B, Hake AM, Murrell JR, Epperson F, Farlow MR, Vidal R, Spina S. Familial Alzheimer disease associated with the V717L amyloid precursor protein gene mutation: Neuropathological characterization. Alzheimers Dement. 2008 Jul;4(4 Suppl):T585.
6. Hooli BV, Mohapatra G, Mattheisen M, Parrado AR, Roehr JT, Shen Y, Gusella JF, Moir R, Saunders AJ, Lange C, Tanzi RE, Bertram L. Role of common and rare APP DNA sequence variants in Alzheimer disease. Neurology. 2012 Apr 17;78(16):1250-7. Epub 2012 Apr 4 PubMed.
7. Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, Mann D, Snowden J, Neary D, Harris J, Bras J, ARUK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 PubMed.
8. De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, Checler F, Annaert W, Van Broeckhoven C, De Strooper B. Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet. 2001 Aug 1;10(16):1665-71. PubMed.
9. 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.
10. Shirotani K, Watanabe K, Hatta D, Kutoku Y, Ohsawa Y, Sunada Y, Kondo T, Inoue H, Iwata N. Alterations of ATG4A and LC3B in neurons derived from Alzheimer's disease patients. Genes Cells. 2023 Apr;28(4):319-325. Epub 2023 Feb 14 PubMed.
11. 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.

Further Reading