Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198040 C>T
Position: (GRCh37/hg19):Chr14:73664748 C>T
dbSNP ID: rs63751420
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to GTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was originally reported in two families of Japanese origin (Rogaev et al., 1995; Ikeda et al., 1996; Poorkaj et al., 1998). In the more well-characterized family, at least 10 members, across three generations, suffered from AD symptoms, usually beginning with personality changes and memory loss at a mean age of 40 years (Ikeda et al., 1996). The mutation was present in all four affected members who were tested, and absent from 140 Japanese and 200 white controls.

The mutation has also been found in several non-Asian families. It was identified in an AD patient in the U.K. with six family members across two generations presenting with AD symptoms beginning at ages 40–42 (Janssen et al., 2003). Moreover, it was found in a woman from the Iberian peninsula who developed AD symptoms at age 30 and had a family history of dementia emerging before age 40 (Guerreiro et al., 2010). The mutation was also found in a member of a French family with six affected individuals with age of onset ranging between 34 and 38 years (Wallon et al., 2012).

Of note, in at least one carrier, the AD phenotype was accompanied by myoclonus and seizures (Ryan et al., 2016). 

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

Neuropathology
In three cases from the Japanese pedigree, neuropathology was consistent with AD, including widespread senile plaques, neurofibrillary tangles, and neuronal loss. In addition, abundant perivascular amyloid deposits were found in the subpial regions of Virchow-Robin spaces and Pick-like intraneuronal inclusions were observed in the dentate gyrus (Ikeda et al., 1996).

In another study, a man who died at age 46 was reported to have diffuse plaques as the most common type of Aβ deposit, found mostly in intermediate cortical layers (Maarouf et al., 2008), Also in this case, amyloid angiopathy was observed in leptomeningeal vessels. The authors noted that, although this individual had high levels of total Aβ and an elevated Aβ42/Aβ40 ratio in the cortex compared with controls, his levels of total Aβ in frontal cortex were low compared with carriers of other PSEN1 mutations and his APOE genotype was APOE2/E3.

Interestingly, six carriers of A260V were reported to have Lewy body pathology (LBP) in the amygdala as assessed by α-synuclein staining, with the pathology extending into the neocortex and cingulate gyrus in five (Leverenz et al., 2006). In four cases, LBP was also found in the substantia nigra, and in two in the medulla.

Biological Effect
In the conditioned media of COS-1 cells transfected with cDNAs encoding APP695 and the A260V mutant, the Aβ42/Aβ ratio was increased relative to controls (Murayama et al., 1999). Consistent with this finding, an in vitro assay using the APP-C99 substrate revealed an approximately 18-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). The mutant produced less of both Aβ42 and Aβ40, but this assay's ability to recapitulate physiological cleavage efficiency appears to be limited (Liu et al., 2021). Decreased Aβ production was also reported in PC12D transfected cells (Kametani et al., 2004).

Amyloid β production was also disrupted in HEK293 cells expressing this variant (Schultz et al., 2023). While the Aβ42/Aβ40 ratio was increased, the ratio of short to long Aβ species was decreased. An indicator of γ-secretase function as a percentage of wildtype activity was developed combining the Aβ (37 + 38 + 40) / (42 + 43) ratio—a measure of γ-processivity—with the commonly used Aβ42/Aβ40 ratio—a measure of the relative production of aggregation-prone Aβ. This composite score, 40.15 for A260V, was strongly associated with AD age at onset, as well as biomarker and cognitive trajectories across multiple PSEN1 variants.

A reduction in Rab8, a GTPase involved in vesicular transport, and disruption of the intracellular distribution of the APP C-terminal fragment was also observed in PC12 cells (Kametani et al., 2004).

The A260V substitution preserves amino acid polarity, but increases the number of side-chain carbon atoms (Soto-Ospina et al., 2021). In silico modeling predicted it severely modifies the structure of the catalytic pore, possibly affecting its accessibility to the APP substrate.

Consistent with these findings, several algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 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.

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References

Paper Citations

1. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PubMed.
2. Ikeda M, Sharma V, Sumi SM, Rogaeva EA, Poorkaj P, Sherrington R, Nee L, Tsuda T, Oda N, Watanabe M, Aoki M, Shoji M, Abe K, Itoyama Y, Hirai S, Schellenberg GD, Bird TD, St George-Hyslop PH. The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients. Ann Neurol. 1996 Dec;40(6):912-7. PubMed.
3. Poorkaj P, Sharma V, Anderson L, Nemens E, Alonso ME, Orr H, White J, Heston L, Bird TD, Schellenberg GD. Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
4. 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.
5. 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.
6. Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, Pariente J, Puel M, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Moreaud O, Gabelle A, Sellal F, Sauvée M, Laquerrière A, Duyckaerts C, Delisle MB, Streichenberger N, Lannes B, Frebourg T, Hannequin D, Campion D. The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
7. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
8. Maarouf CL, Daugs ID, Spina S, Vidal R, Kokjohn TA, Patton RL, Kalback WM, Luehrs DC, Walker DG, Castaño EM, Beach TG, Ghetti B, Roher AE. Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. Mol Neurodegener. 2008 Nov 20;3:20. PubMed.
9. Leverenz JB, Fishel MA, Peskind ER, Montine TJ, Nochlin D, Steinbart E, Raskind MA, Schellenberg GD, Bird TD, Tsuang D. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
10. Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
11. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
12. Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
13. Kametani F, Usami M, Tanaka K, Kume H, Mori H. Mutant presenilin (A260V) affects Rab8 in PC12D cell. Neurochem Int. 2004 Apr;44(5):313-20. PubMed.
14. Schultz S, Liu L, Schultz A, Fitzpatrick C, Levin R, Bellier J-P, Shirzadi Z, Mathurin N, Chen C, Benzinger T, Day G, Farlow M, Gordon B, Hassenstab J, Jack C, Jucker M, Karch C, Lee J, Levin J, Perrin R, Schofield P, Xiong C, Johnson K, McDade E, Bateman R, Sperling R, Selkoe D, Chhatwal J, theDominantlyInheritedAlzheimer'sNetworkInvestigators. Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
15. Soto-Ospina A, Araque Marín P, Bedoya G, Sepulveda-Falla D, Villegas Lanau A. Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer's Disease on the Orthosteric Site. Front Mol Biosci. 2021;8:649990. Epub 2021 Jun 2 PubMed.
16. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. gnomAD v2.1.1

Further Reading