Mutations

APP V717I (London)

Other Names: London

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Spastic Paraparesis
Position: (GRCh38/hg38):Chr21:25891784 G>A
Position: (GRCh37/hg19):Chr21:27264096 G>A
dbSNP ID: rs63750264
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to ATC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17
Research Models: 27

Findings

This mutation was one of the first described in APP. It was originally identified in 1991 in an English kindred with early onset Alzheimer's disease, identified as family F23. The average age of onset in this family was 57 ± 5 years and the diagnosis was confirmed by autopsy. In the same publication, an American family known as family 372 was also reported to carry this mutation (Goate et al., 1991; Hardy et al., 1991). Cosegregation with disease was established, including the identification of five affected carriers and multiple unaffected non-carriers in the same family.

This mutation appears to be one of the most common APP mutations worldwide, with more than 30 families identified from various countries of origin, including the United States, England, Japan, Thailand, Germany, France, Italy, Australia, Belgium, Iran, and China. Interestingly, a study of five Han Chinese families suggested the clinical phenotype associated with this mutation may vary with ancestry and/or environmental factors (Zhang et al., 2017). Most of the carriers in the Chinese families (77 percent) had affective symptoms at disease onset, with 53 percent having executive dysfunction and 47 percent disorientation. In addition, the Chinese carriers frequently developed spastic paraparesis (38 percent) and cerebellar ataxia (35 percent). Also of note, the mean age at onset was 55 years, with onset occurring earlier in APOE4 carriers.

APP V717I was absent from the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology

The neuropathological phenotype associated with the London mutation is variable. For the original English family, neuropathological findings were available for one individual who had severe AD pathology along with mild amyloid angiopathy and cortical and brainstem Lewy bodies. In the American family, numerous β-amyloid plaques and neurofibrillary tangles were observed, but no amyoid angiopathy or Lewy bodies (Hardy et al., 1991).

Another carrier, a Caucasian female, had pronounced and widespread cerebral amyloid angiopathy (CAA), as well as TDP-43 pathology in the hippocampus and amygdala consistent with limbic predominant age-related TDP-43 proteinopathy (LATE) (Lloyd et al., 2020). This carrier had an APOE2/E3 genotype which the authors hypothesize might have contributed to the severe vascular pathology.

Yet another carrier, a Japanese woman with AD dementia, had abundant amyloid deposition in the striatum, but minimal amyloid deposition in the cortex as assessed by PET imaging (Kobayashi et al., 2022). Cortical amyloid remained low even after years of cognitive decline.

Biological Effect

The effects of this mutation have been well-characterized. In many cells types, including primary mouse neurons, this mutation increases the Aβ42/Aβ40 ratio by increasing Aβ42 levels with little effect on Aβ40 levels (e.g. Eckman et al., 1997; De Jonghe et al., 2001; Theuns et al., 2006; Herl et al., 2009). This finding has also been observed in neurons generated from inducible pluripotent stem cells (iPSCs) derived from the skin fibroblasts of mutation carriers and differentiated into forebrain neurons. In addition to increasing Aβ42 levels, the V717I mutation in these neurons altered APP subcellular localization, Aβ38 and sAPPβ generation, and tau expression and phosphorylation (Muratore et al., 2014). A study that monitored Aβ peptides produced by γ-secretase cleavage of APP in vitro, revealed V717I generates higher levels of all Aβ peptides, particularly longer, membrane-anchored species that may be pathogenic, and particularly those in the Aβ48 → Aβ45 → Aβ42 → Aβ38 pathway (Devkota et al., 2021, Feb 2021 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 three PSEN1 residues (Zhou et al., 2019; Jan 2019 news), and computational simulations suggest the V717I mutation loosens the binding between the two proteins, increasing the tilt of the APP transmembrane helix, and shifting the substrate away from the ε cleavage site (Dehury et al., 2020). Consistent with this prediction, data from a yeast model system designed to quantitatively assess APP cleavage indicated V717I moderately reduces ε-cleavage (Suzuki et al., 2023). This is in contrast, however, with in vitro experiments indicating the mutation increases ε-cleavage (Devkota et al., 2021). Devkota and colleagues also reported a shift in ε-cleavage in favor of Aβ48 relative to Aβ49.

V717I's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

Research models
Several rodent models carrying this mutation, as well as human iPSC lines derived from patient carriers (e.g., Muratore et al., 2014; Sun et al., 2023a), including an iPSC line from a homozygous carrier (Wei et al., 2022), have been created. Furthermore, neuronal cell models have been generated directly from adult fibroblasts (Sun et al., 2023b, Jun 2023 news). Unlike neurons differentiated from induced pluripotent stem cells, these transdifferentiated neurons, called tNeurons, retained epigenetic marks of aging.

V717I iPSCs have been used to generate a long-lived 3D tissue model which recapitulated AD-associated phenotypes that progressed over time (Lomoio et al., 2022).

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.

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. V717I: 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.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. V717I: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

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)

Last Updated: 10 Nov 2023

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References

News Citations

  1. Are the Long Aβ Peptides the Real Bad Guys?
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  3. Better Cell Model? Transdifferentiated Neurons Capture AD-Like Changes

Paper Citations

  1. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704-6. PubMed.
  2. Molecular classification of Alzheimer's disease. Lancet. 1991 Jun 1;337(8753):1342-3. PubMed.
  3. Zhang G, Xie Y, Wang W, Feng X, Jia J. Clinical characterization of an APP mutation (V717I) in five Han Chinese families with early-onset Alzheimer's disease. J Neurol Sci. 2017 Jan 15;372:379-386. Epub 2016 Oct 28 PubMed.
  4. Lloyd GM, Trejo-Lopez JA, Xia Y, McFarland KN, Lincoln SJ, Ertekin-Taner N, Giasson BI, Yachnis AT, Prokop S. Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier - phenotypic variability in autosomal dominant Alzheimer's disease. Acta Neuropathol Commun. 2020 Mar 12;8(1):31. PubMed.
  5. Kobayashi R, Kawakatsu S, Hayashi H, Morioka D, Hara N, Ikeuchi T, Otani K. Focal striatal amyloid deposition in Alzheimer's disease caused by APP p.V717I mutation: Longitudinal positron emission tomography study. Geriatr Gerontol Int. 2022 Apr;22(4):360-362. Epub 2022 Feb 24 PubMed.
  6. Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeiffer E, Graff-Radford N, Hinder P, Yager D, Zenk B, Refolo LM, Prada CM, Younkin SG, Hutton M, Hardy J. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet. 1997 Nov;6(12):2087-9. PubMed.
  7. 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.
  8. Theuns J, Marjaux E, Vandenbulcke M, Van Laere K, Kumar-Singh S, Bormans G, Brouwers N, Van den Broeck M, Vennekens K, Corsmit E, Cruts M, De Strooper B, Van Broeckhoven C, Vandenberghe R. Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment. Hum Mutat. 2006 Sep;27(9):888-96. PubMed.
  9. Herl L, Thomas AV, Lill CM, Banks M, Deng A, Jones PB, Spoelgen R, Hyman BT, Berezovska O. Mutations in amyloid precursor protein affect its interactions with presenilin/gamma-secretase. Mol Cell Neurosci. 2009 Jun;41(2):166-74. Epub 2009 Mar 9 PubMed.
  10. Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LN, Walsh DM, Selkoe DJ, Young-Pearse TL. The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet. 2014 Jul 1;23(13):3523-36. Epub 2014 Feb 12 PubMed.
  11. 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.
  12. 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.
  13. Dehury B, Somavarapu AK, Kepp KP. A computer-simulated mechanism of familial Alzheimer's disease: Mutations enhance thermal dynamics and favor looser substrate-binding to γ-secretase. J Struct Biol. 2020 Dec 1;212(3):107648. Epub 2020 Oct 21 PubMed.
  14. Suzuki R, Takahashi H, Yoshida C, Hidaka M, Ogawa T, Futai E. Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production. Int J Mol Sci. 2023 Feb 16;24(4) PubMed.
  15. Sun W, Wang P, Gong J, Chen Y, Yang Y, Luan H, Li S, Li R, Wei C. Generation of induced pluripotent stem cell line (XWHNi002-A) from a female with APP gene mutation. Stem Cell Res. 2023 Sep;71:103149. Epub 2023 Jun 21 PubMed.
  16. Wei C, Lu X, Zou Q, Gong S, Chen Y, Lyu J, Jia J. Generation and characterization of a human induced pluripotent stem cell line (XWHNi001-A) derived from an Alzheimer's disease patient with mutation in the APP gene. Stem Cell Res. 2022 Apr;60:102690. Epub 2022 Jan 31 PubMed.
  17. 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.
  18. Lomoio S, Pandey RS, Rouleau N, Menicacci B, Kim W, Cantley WL, Haydon PG, Bennett DA, Young-Pearse TL, Carter GW, Kaplan DL, Tesco G. 3D bioengineered neural tissue generated from patient-derived iPSCs mimics time-dependent phenotypes and transcriptional features of Alzheimer's disease. Mol Psychiatry. 2023 Jun 26; PubMed.

Other Citations

  1. rodent models

Further Reading

Papers

  1. Yoshioka K, Miki T, Katsuya T, Ogihara T, Sakaki Y. The 717Val----Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups. Biochem Biophys Res Commun. 1991 Aug 15;178(3):1141-6. PubMed.
  2. Naruse S, Igarashi S, Kobayashi H, Aoki K, Inuzuka T, Kaneko K, Shimizu T, Iihara K, Kojima T, Miyatake T. Mis-sense mutation Val----Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease. Lancet. 1991 Apr 20;337(8747):978-9. PubMed.
  3. Fidani L, Rooke K, Chartier-Harlin MC, Hughes D, Tanzi R, Mullan M, Roques P, Rossor M, Hardy J, Goate A. Screening for mutations in the open reading frame and promoter of the beta-amyloid precursor protein gene in familial Alzheimer's disease: identification of a further family with APP717 Val-->Ile. Hum Mol Genet. 1992 Jun;1(3):165-8. PubMed.
  4. Sorbi S, Nacmias B, Forleo P, Piacentini S, Amaducci L, Provinciali L. APP717 and Alzheimer's disease in Italy. Nat Genet. 1993 May;4(1):10. PubMed.
  5. Yoshizawa T, Komatsuzaki Y, Iwamoto H, Mizusawa H, Kanazawa I. Screening of the mis-sense mutation producing the 717Val-->Ile substitution in the amyloid precursor protein in Japanese familial and sporadic Alzheimer's disease. J Neurol Sci. 1993 Jul;117(1-2):12-5. PubMed.
  6. Sorbi S, Nacmias B, Forleo P, Piacentini S, Latorraca S, Amaducci L. Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease. Ann Neurol. 1995 Jul;38(1):124-7. PubMed.
  7. Brooks WS, Martins RN, De Voecht J, Nicholson GA, Schofield PR, Kwok JB, Fisher C, Yeung LU, Van Broeckhoven C. A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease. Neurosci Lett. 1995 Oct 27;199(3):183-6. PubMed.
  8. Matsumura Y, Kitamura E, Miyoshi K, Yamamoto Y, Furuyama J, Sugihara T. Japanese siblings with missense mutation (717Val --> Ile) in amyloid precursor protein of early-onset Alzheimer's disease. Neurology. 1996 Jun;46(6):1721-3. PubMed.
  9. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  10. Campion D, Brice A, Hannequin D, Charbonnier F, Dubois B, Martin C, Michon A, Penet C, Bellis M, Calenda A, Martinez M, Agid Y, Clerget-Darpoux F, Frebourg T. No founder effect in three novel Alzheimer's disease families with APP 717 Val-->Ile mutation. Clerget-darpoux. French Alzheimer's Disease Study Group. J Med Genet. 1996 Aug;33(8):661-4. PubMed.
  11. Finckh U, Müller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PubMed.
  12. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  13. 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.
  14. Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  15. Brouwers N, Sleegers K, Engelborghs S, Bogaerts V, Serneels S, Kamali K, Corsmit E, De Leenheir E, Martin JJ, De Deyn PP, Van Broeckhoven C, Theuns J. Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease. Brain. 2006 Nov;129(Pt 11):2984-91. PubMed.
  16. Tedde A, Nacmias B, Ciantelli M, Forleo P, Cellini E, Bagnoli S, Piccini C, Caffarra P, Ghidoni E, Paganini M, Bracco L, Sorbi S. Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  17. Jiao B, Tang B, Liu X, Xu J, Wang Y, Zhou L, Zhang F, Yan X, Zhou Y, Shen L. Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. Neurobiol Aging. 2014 Aug;35(8):1957.e1-6. Epub 2014 Feb 20 PubMed.
  18. 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.
  19. Noroozian M, Azadfar P, Akbari L, Sadeghi A, Houshmand M, Vousooghi N, Zarrindast MR, Minagar A. Early-onset Alzheimer's disease in two Iranian families: a genetic study. Dement Geriatr Cogn Disord. 2014;38(5-6):330-6. Epub 2014 Aug 14 PubMed.
  20. Katsuya T, Miki T, Tanabe H, Takeda M, Hosokawa K, Hayashi H, Hashimoto S, Nishimura T, Ogihara T. [Affected siblings with Alzheimer's disease had missense mutation of codon 717 in amyloid precursor protein gene]. Nihon Ronen Igakkai Zasshi. 1992 Feb;29(2):129-34. PubMed.
  21. Imagawa M, Naruse S, Tsuji S, Fujioka A, Yamaguchi H. Coenzyme Q10, iron, and vitamin B6 in genetically-confirmed Alzheimer's disease. Lancet. 1992 Sep 12;340(8820):671. PubMed.
  22. Barber IS, García-Cárdenas JM, Sakdapanichkul C, Deacon C, Zapata Erazo G, Guerreiro R, Bras J, Hernandez D, Singleton A, Guetta-Baranes T, Braae A, Clement N, Patel T, Brookes K, Medway C, Chappell S, Mann DM, ARUK Consortium, Morgan K. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease. Neurobiol Aging. 2016 Mar;39:220.e1-7. Epub 2015 Dec 29 PubMed.
  23. Sun L, Zhang J, Su N, Zhang S, Yan F, Lin X, Yu J, Li W, Li X, Xiao S. Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing. Front Aging Neurosci. 2021;13:745407. Epub 2021 Oct 14 PubMed.
  24. Singer MB, Ringman JM, Chu Z, Zhou X, Jiang X, Shahidzadeh A, Wang RK, Kashani AH. Abnormal retinal capillary blood flow in autosomal dominant Alzheimer's disease. Alzheimers Dement (Amst). 2021;13(1):e12162. Epub 2021 Mar 4 PubMed.
  25. Mol MO, van der Lee SJ, Hulsman M, Pijnenburg YA, Scheltens P, Netherlands Brain Bank, Seelaar H, van Swieten JC, Kaat LD, Holstege H, van Rooij JG. Mapping the genetic landscape of early-onset Alzheimer's disease in a cohort of 36 families. Alzheimers Res Ther. 2022 Jun 1;14(1):77. PubMed.

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704-6. PubMed.

Other mutations at this position

View Table

Alzpedia

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