Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27264099 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to TTC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17
Research Models: 4

Findings

This mutation was first detected in a Caucasian patient of Spanish or Portuguese ancestry who was diagnosed with probable Alzheimer's disease according to DSM-IV and NINCDS-ADRDA criteria. Clinical symptoms began at age 31 and the patient died two years later. The patient had a family history of AD, although it was not possible to evaluate segregation of the mutation with disease (Guerreiro et al., 2010).

This mutation was later reported in two members of a Kurdish family affected by a familial dementia syndrome described as reminiscent of Creutzfeldt-Jakob disease because it involved prominent cerebellar ataxia and other motor features in addition to rapid cognitive decline (Sieczkowski et al., 2015). The reported pedigree shows five affected family members over four generations. The proband developed symptoms at age 47, starting with gait disturbance and uncoordinated jerky movements of the right arm. He had a three-year history of severe depression. Within one year of developing motor symptoms, he developed rapid cognitive decline and dementia. He developed seizures and was bedridden at age 49. He died at age 55. His brother had died at age 37 with a diagnosis of CJD following a similar disease course. No autopsy was performed. The proband’s mother had died in her 30s with dementia, but further clinical details were not available. The proband’s niece, who also carried the mutation, showed signs of cognitive decline at the time of the report. 

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

Neuropathology

The I716F mutation is associated with extensive and often mixed neuropathology, characterized by typical AD pathology (e.g., amyloid plaques and neurofibrillary tangles), in addition to α-synuclein pathology in some cases. For example, in one case, primarily AD pathology was observed, namely neurofibrillary changes (Braak stage VI) and amyloid deposits (CERAD stage C) (Guerreiro et al., 2010). In another case, Lewy bodies were observed in the amygdala along with abundant diffuse amyloid plaques, composed mainly of Aβ42, and widespread neurofibrillary pathology (Guardia-Laguarta et al., 2010).

In the Kurdish proband, a detailed neuropathological examination revealed extensive amyloid, tau, and α-synuclein pathology, but no deposits of TDP-43, FUS, or PrP. Amyloid pathology consisted of abundant cored and diffuse plaques throughout the cortex in addition to some cerebral amyloid angiopathy in the vasculature (CERAD stage C). Notably, N-truncated pyroglutamate-modified Aβ peptides were observed, including within Purkinje cells. Tau pathology consisted of neurofibrillary tangles, dystrophic neurites, and neuropil threads, especially prominent in the neocortex, hippocampal formation, and thalamus (Braak stage VI). Alpha-synuclein pathology was most prominent in the amygdala, temporal cortex, hippocampal formation, brainstem, and basal ganglia. The abundant Lewy body pathology in these regions was consistent with Parkinson's disease stage 6 (Braak et al., 2003) and fulfilled criteria for dementia with Lewy bodies (McKeith et al., 2005). Spongiosis was also observed in the superficial layers of the frontal and parietal cortices along with reactive astrogliosis (Sieczkowski et al., 2015).

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

Biological Effect

Many years before this mutation was detected in a patient, an I to F amino acid change at this position was shown experimentally to affect APP cleavage by γ-secretase. Specifically, it was shown that when the isoleucine residue was altered to phenylalanine, the amino acid change, referred to as I45F, affected γ-secretase cleavage specificity and caused a dramatic increase in the Aβ42/Aβ40 ratio (Lichtenthaler et al., 1999). Consistent with this effect on Aβ production, an elevated Aβ42/Aβ40 ratio was reported in CHO cells as well as increased APP C-terminal fragments and decreased APP intracellular domain production (Herl et al., 2009; Guardia-Laguarta et al., 2010). A cryo-electron microscopy study of PSEN1 bound to a fragment of APP indicates V716F may enhance production of Aβ48, the first product of the γ-secretase cleavage line Aβ48-Aβ45-Aβ42-Aβ38, by stabilizing the local APP structure (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.

Research Models

This mutation has been introduced into several AD mouse models, including two knock-in models (APP^NL-F and APP^NL-G-F). The presence of the I716F mutation in these models significantly increases the ratio of Aβ42 to Aβ40_. These knock-in mice, which also harbor additional APP mutations, develop amyloid plaques, gliosis, and cognitive impairment, but not tangles or neurodegeneration. They are considered advantageous models for studying the effects of pathological levels of Aβ in the context of physiological levels of APP.

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References

Research Models Citations

1. APP NL-F Knock-in
2. APP NL-G-F Knock-in

News Citations

1. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
2. Sieczkowski E, Milenkovic I, Venkataramani V, Giera R, Ströbel T, Höftberger R, Liberski PP, Auff E, Wirths O, Bayer TA, Kovacs GG. I716F AβPP Mutation Associates with the Deposition of Oligomeric Pyroglutamate Amyloid-β and α-Synucleinopathy with Lewy Bodies. J Alzheimers Dis. 2015 Jan 1;44(1):103-14. PubMed.
3. Guardia-Laguarta C, Pera M, Clarimón J, Molinuevo JL, Sánchez-Valle R, Lladó A, Coma M, Gómez-Isla T, Blesa R, Ferrer I, Lleó A. Clinical, neuropathologic, and biochemical profile of the amyloid precursor protein I716F mutation. J Neuropathol Exp Neurol. 2010 Jan;69(1):53-9. PubMed.
4. Braak H, Del Tredici K, Rüb U, De Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. PubMed.
5. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005 Dec 27;65(12):1863-72. PubMed.
6. Lichtenthaler SF, Wang R, Grimm H, Uljon SN, Masters CL, Beyreuther K. Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3053-8. PubMed.
7. 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.
8. 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

No Available Further Reading