Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Position: (GRCh38/hg38):Chr14:73192799 T>C
Position: (GRCh37/hg19):Chr14:73659507 T>C
dbSNP ID: rs63749835
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to CCG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7
Research Models: 1

Findings

This mutation was first reported in a French family, SAL 510, with familial early onset Alzheimer’s disease (Campion et al., 1996). As reported, this family had four affected individuals who met NINCDS-ADRDA criteria for probable or definite AD. The mutation segregated with disease in this family: three affected siblings were heterozygous carriers and two unaffected siblings were not carriers. Age of onset in this family ranged from 29 to 35 (mean: 32.5 years). A subsequent study that expanded on this report described five affected family members over three generations, with a revised age of onset ranging from 29-39 years (Campion et al., 1999). Symptoms included progressive memory and language impairment, tonic-clonic seizures, neurological signs (including Babinski), and myoclonus. Disease progression was rapid, with severe dementia within a few years of symptom onset. The clinical picture in this family was notable for the presence of seizures, typically starting in childhood or early adolescence. However, the authors note that the seizures did not always co-occur with dementia, and that a second genetic variant predisposing to epilepsy may be responsible. Interestingly, in another study of French individuals, seizures were reported in two of three carriers of this mutation (Zarea et al. 2016). 

In addition, the L235P was found in a patient of German origin, known as P.54. The patient experienced onset of dementia at age 32. Her mother died at age 34 with an autopsy-confirmed diagnosis of AD. A great-grandparent of P.54 was of French ancestry, leading the authors to speculate a possible French founder effect for this mutation given the discovery of the mutation in the French SAL 510 family (Finckh et al., 2005).

The L235P mutation was also reported in a Mexican family with mean age at onset of 37 years (Llibre-Guerra et al., 2021), as well as in an individual with AD, but clinical details, demographic information, and family history were not described (Rogaeva et al., 2001). 

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

Neuropathology

Neuropathology consistent with AD has been observed in four affected mutation carriers (Campion et al., 1996; Cash et al., 2021). Postmortem examination of one carrier showed a high density of senile plaques and neurofibrillary tangles in the cerebral cortex and hippocampus (Campion et al., 1996). Spongiosis was noted in layer 2. Tangles were observed also in the basal nucleus of Meynert, septal and raphe nuclei, and the locus coeruleus. Another study noted the association of acetylcholinesterase and butyrylcholinesterase with plaques and tangles, similar to that observed in sporadic AD, in three carriers belonging to the same family (Cash et al., 2021). In one case, α-synuclein pathology was also identified, but it was not associated with cholinesterases.

Biological Effect

Expression in transgenic mice was associated with increased production of Aβ, increased tau hyperphosphorylation, and loss of synaptic protein (Yang et al., 2012). Studies that surveyed Aβ production in cell cultures revealed decreases in the Aβ (37 + 38 + 40) / (42 + 43) ratio and the Aβ37/Aβ42 ratio, both of which reflect γ-processivity, compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). The two ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset.

An in vitro assay using purified proteins showed reductions in Aβ42, and particularly Aβ40, production (Sun et al., 2017). However, this assay appears to be limited in its cleavage efficiency given that 68 of 138 mutant recombinant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

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).

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 the APP751SL/PS1 KI double mutant, which also expresses APP with the London (V717I) and Swedish (K670N/M671L) mutations.

In a single transgenic mouse model, the L235P mutation was associated with increased production of Aβ, increased tau hyperphosphorylation, and loss of synaptic proteins (Yang et al., 2012).

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References

Research Models Citations

1. APP751SL/PS1 KI

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022

Paper Citations

1. Yang X, Yang Y, Liu J, Li G, Yang E. Increased phosphorylation of tau and synaptic protein loss in the aged transgenic mice expressing familiar Alzheimer's disease-linked presenilin 1 mutation. Neurochem Res. 2012 Jan;37(1):15-22. PubMed.
2. Campion D, Brice A, Dumanchin C, Puel M, Baulac M, De La Sayette V, Hannequin D, Duyckaerts C, Michon A, Martin C, Moreau V, Penet C, Martinez M, Clerget-Darpoux F, Agid Y, Frebourg T. A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. Neuroreport. 1996 Jul 8;7(10):1582-4. 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. Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
5. 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.
6. Llibre-Guerra JJ, Li Y, Allegri RF, Mendez PC, Surace EI, Llibre-Rodriguez JJ, Sosa AL, Aláez-Verson C, Longoria EM, Tellez A, Carrillo-Sánchez K, Flores-Lagunes LL, Sánchez V, Takada LT, Nitrini R, Ferreira-Frota NA, Benevides-Lima J, Lopera F, Ramírez L, Jiménez-Velázquez I, Schenk C, Acosta D, Behrens MI, Doering M, Ziegemeier E, Morris JC, McDade E, Bateman RJ. Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes. Alzheimers Dement. 2021 Apr;17(4):653-664. Epub 2020 Nov 23 PubMed.
7. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
8. Cash MK, Rockwood K, Fisk JD, Darvesh S. Clinicopathological correlations and cholinesterase expression in early-onset familial Alzheimer's disease with the presenilin 1 mutation, Leu235Pro. Neurobiol Aging. 2021 Jul;103:31-41. Epub 2021 Mar 4 PubMed.
9. Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
10. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; 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. 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

No Available Further Reading