Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Atypical Dementia, Progressive Nonfluent Aphasia, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73198052 C>T
Position: (GRCh37/hg19):Chr14:73664760 C>T
dbSNP ID: rs63750301
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to CTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8
Research Models: 1

Findings

This mutation has been detected in at least 13 families worldwide, with a variable, and often atypical, presentation of Alzheimer’s disease. The diversity of phenotypic expression associated with the P264L mutation is unusual and includes spastic paraparesis, dementia with Lewy bodies, atypical dementia, lobar hemorrhage, and non-fluent primary progressive aphasia.

The P264L mutation was first reported in 1995 in a French kindred known as SAL 511. As reported, the family contained six affected individuals with age of onset ranging from 45 to 56. The mutation was shown to segregate with disease (Campion et al., 1995). Affected family members were diagnosed with AD according to NINCDS-ADRDA criteria, but they also frequently presented with atypical features such as myoclonus, extrapyramidal signs, and seizures. Neuropathological examination revealed plaque and tangle pathology consistent with a diagnosis of AD in at least two family members (Campion et al., 1995). This family was also analyzed in Campion et al., 1999, along with two other French families known as SAL 506 and SAL 1633, both with four affected individuals in three generations. Ages of onset in these families were 46 to 52 and 51 to 55 years, respectively. The clinical presentation in the SAL 1633 family was notable for a spastic paraparesis phenotype. At least three additional French families have been identified, and are also reported to be commonly affected by spastic paraparesis (Raux et al., 2005; Jacquemont et al., 2002; Dumanchin et al., 2006).

Several additional families with this mutation have been reported. One pedigree, known as MGH6, consisted of two affected siblings with onset at ages 45 and 50 years, the former confirmed as a mutation carrier (Wasco et al., 1995). The sibling of the carrier had autopsy-confirmed AD. Several age-matched, unaffected members of the family did not carry the mutation. A pedigree known as EOFAD-6 had a mean age of onset of 39 years and autopsy-confirmed AD (Kwok et al., 1997). A British kindred known as KG has been reported with five reported affected individuals, three with autopsy-confirmed AD, and an overall age of onset ranging from 41 to 45 years (Poorkaj et al., 1998). Similar to the previously reported French families, an additional P264L kindred of unspecified origins had at least one family member affected by spastic paraparesis. Another member in this family met clinical criteria for dementia with Lewy bodies, while another displayed symptoms more typical of AD (Martikainen et al., 2010).

More recently, a Turkish family known as DEM-9 was found to carry this mutation. The proband in this family developed memory problems and personality changes at the age of 51; her mother reportedly had been affected at age 60. The proband's brother, who also carried the mutation, did not report subjective memory difficulties at the age of 51, although significant impairments were noted by specialized neuropsychological tests. He had a university degree and worked as an engineer, suggesting that cognitive reserve may have delayed functional impairment in this case (Lohmann et al., 2012).

Further highlighting the variability of this mutation, two Japanese siblings carrying the P264L mutation presented with different phenotypes, one with atypical AD with features of frontotemporal dementia, and the other with typical AD based on clinical symptoms and brain imaging (Ishizuka et al., 2012).

Finally, the occurrence of non-fluent primary progressive aphasia in one mutation carrier from the United Kingdom rounds out the clinical heterogeneity associated with P264L. The patient presented at age 45 with a three-year history of progressive speech and word-finding difficulties. Her father had developed cognitive decline around age 60 with insidious behavioral changes and episodic memory difficulties. As he was predeceased, it is unknown if he carried the mutation (Mahoney et al., 2013).

This variant was present in the gnomAD variant database, but with an allele count of only 1 (gnomAD v2.1.1, July 2021) and a frequency of 0.000003997. It was absent from the non-neuro gnomAD dataset which excludes individuals from neurological studies.

Neuropathology

Like the clinical presentation associated with this mutation, the associated neuropathology is variable. One patient had significant white-matter abnormalities. Another suffered a right occipital hemorrhage four years after dementia onset. In a third, neuropathology was consistent with a diagnosis of AD (Braak stage VI), but also included severe cerebral amyloid angiopathy with numerous small infarcts in the cortex (Dumanchin et al., 2006). Detailed neuropathology for three affected mutation carriers within a single family has been described (Martikainen et al., 2010). In brief, the authors observed abundant cotton-wool plaques composed of Aβ42 but also containing hyperphosphorylated tau, and in one case TDP-43. The distribution of the pathology varied, but associations were observed between neocortical/thalamic involvement and psychiatric symptoms, between striatal/amygdaloid involvement and Parkinsonism, and between brainstem involvement and spastic paraparesis.

Biological Effect

In vitro, the P264L mutation is associated with an increase in the Aβ42/Aβ40 ratio (Murayama et al., 1999; Ben-Gedalya et al., 2015; Sun et al., 2017). Sun et al. reported a greater than five-fold increase in the ratio (Sun et al., 2017), but the effect was not significant under all experimental conditions (see Dumanchin et al., 2006). The mutation does not appear to affect the splicing of exon 9 within PSEN1 (Dumanchin et al., 2006).

In assays using membrane samples isolated from the brain of a mutation carrier, the Aβ42/Aβ40 ratio was also found to be elevated, with reduced de novo production of Aβ40 and Aβ38, and increased production of Aβ42 (Szaruga et al., 2015). The reduction of the Aβ38/Aβ42 ratio suggests impairment of the fourth catalytic cleavage in the carboxypeptidase-like digestion of Aβ into shorter peptides. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue appears to help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

This mutation was also reported to abolish a recognition site for cyclophilin B, a chaperone protein in the endoplasmic reticulum that assists with PSEN1 folding and maturation (Ben-Gedalya et al., 2015). The destruction of the recognition site appears to result in PSEN-1 aggregation and deposition within the ER, leading to reduced γ-secretase activity and a significant increase in the ratio of secreted Aβ42/Aβ40. 

P264L may also disrupt other cellular functions relevant to AD. It has been shown to impair mitochondrial activity and ATP production (Ben-Gedalya et al., 2015). Moreover, in one carrier with an APOE3/3 genotype, blood ApoE levels were reduced compared with those of non-carriers (Islam et al., 2022). This may be due to a disruption of PSEN1’s proposed role in ApoE secretion.

Several in silico 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).

Based on the AMCG-AMP guidelines, Koriath and colleagues classified this variant as deleterious (Koriath et al., 2018) and Xiao and co-workers as pathogenic (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.

Research Models

This mutation has been introduced into mouse models of disease, including PS1 P264L.

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References

News Citations

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

Paper Citations

1. Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
2. Campion D, Brice A, Hannequin D, Tardieu S, Dubois B, Calenda A, Brun E, Penet C, Tayot J, Martinez M. A large pedigree with early-onset Alzheimer's disease: clinical, neuropathologic, and genetic characterization. Neurology. 1995 Jan;45(1):80-5. PubMed.
3. 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.
4. 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.
5. Jacquemont ML, Campion D, Hahn V, Tallaksen C, Frebourg T, Brice A, Durr A. Spastic paraparesis and atypical dementia caused by PSEN1 mutation (P264L), responsible for Alzheimer's disease. J Med Genet. 2002 Feb;39(2):E2. PubMed.
6. Dumanchin C, Tournier I, Martin C, Didic M, Belliard S, Carlander B, Rouhart F, Duyckaerts C, Pellissier JF, Latouche JB, Hannequin D, Frebourg T, Tosi M, Campion D. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.
7. Wasco W, Pettingell WP, Jondro PD, Schmidt SD, Gurubhagavatula S, Rodes L, DiBlasi T, Romano DM, Guenette SY, Kovacs DM. Familial Alzheimer's chromosome 14 mutations. Nat Med. 1995 Sep;1(9):848. PubMed.
8. Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.
9. 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.
10. Martikainen P, Pikkarainen M, Pöntynen K, Hiltunen M, Lehtovirta M, Tuisku S, Soininen H, Alafuzoff I. Brain pathology in three subjects from the same pedigree with presenilin-1 (PSEN1) P264L mutation. Neuropathol Appl Neurobiol. 2010 Feb;36(1):41-54. Epub 2009 Oct 22 PubMed.
11. Lohmann E, Guerreiro RJ, Erginel-Unaltuna N, Gurunlian N, Bilgic B, Gurvit H, Hanagasi HA, Luu N, Emre M, Singleton A. Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
12. Ishizuka T, Nakamura M, Ichiba M, Fujita S, Takeuchi K, Fujimoto T, Sano A. Different Clinical Phenotypes in Siblings with a Presenilin-1 P264L Mutation. Dement Geriatr Cogn Disord. 2012;33(2-3):132-40. PubMed.
13. Mahoney CJ, Downey LE, Beck J, Liang Y, Mead S, Perry RJ, Warren JD. The Presenilin 1 P264L Mutation Presenting as non-Fluent/Agrammatic Primary Progressive Aphasia. J Alzheimers Dis. 2013 Jan 1;36(2):239-43. PubMed.
14. 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.
15. Ben-Gedalya T, Moll L, Bejerano-Sagie M, Frere S, Cabral WA, Friedmann-Morvinski D, Slutsky I, Burstyn-Cohen T, Marini JC, Cohen E. Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction. EMBO J. 2015 Nov 12;34(22):2820-39. Epub 2015 Oct 5 PubMed.
16. 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.
17. Szaruga M, Veugelen S, Benurwar M, Lismont S, Sepulveda-Falla D, Lleo A, Ryan NS, Lashley T, Fox NC, Murayama S, Gijsen H, De Strooper B, Chávez-Gutiérrez L. Qualitative changes in human γ-secretase underlie familial Alzheimer's disease. J Exp Med. 2015 Nov 16;212(12):2003-13. Epub 2015 Oct 19 PubMed.
18. 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.
19. Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M. Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 PubMed.
20. 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.
21. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.
22. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.

Other Citations

1. PS1 P264L

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading