Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Corticobasal Syndrome : Not Classified
ACMG/AMP Pathogenicity Criteria: PS2, PS3, PM1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Corticobasal Syndrome, Myoclonus, Parkinsonism, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73170963 T>C
Position: (GRCh37/hg19):Chr14:73637671 T>C
dbSNP ID: rs63750599
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to CCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This missense mutation in exon 4 was first identified in a young Japanese man living in the United States. While a college student in his early 20s, the proband developed early onset dementia with spastic paraparesis. Sequence analysis revealed a PSEN1 mutation; no other mutations in the coding regions of PSEN1, PSEN2, or APP were detected. The patient’s parents and two siblings did not carry the L85P mutation or any other mutation in PSEN1, PSEN2, or APP. The fact that neither parent was a mutation carrier suggests that it may be a rare de novo mutation. In addition to progressive impairment of intelligence and memory, neuropsychological evaluation of the patient revealed a complex visual problem not attributable to abnormalities of optic fundi, visual acuity, visual field, or color identification. Thus, the patient was thought to have a visual variant of AD (see Levine et al., 1993) rather than typical AD (Ataka et al., 2004).

The mutation was also identified in a 29-year-old woman of Romanian descent presenting with possible corticobasal syndrome (López-García et al., 2019). She suffered from asymmetric limb apraxia, parkinsonian signs, and myoclonus. The first symptoms included depressed mood and impairment of short-term memory. The patient also carried a variant in the SPAST gene, P45Q, which was reported as of uncertain pathogenicity. Of note, more than 240 mutations in SPAST, which encodes a microtubule regulator, cause spastic paraplegia type 4.

Neuropathology

Neuropathological examination was not available. In the Japanese patient, single-photon emission computed tomography (SPECT) and PET showed bilateral hypoperfusion and hypometabolism in the occipital and temporal lobes (Ataka et al., 2004). In the Romanian patient, brain MRI showed symmetric, mild diffuse cortical and subcortical atrophy with subtle parietal predominance (López-García et al., 2019). In addition, a decrease in dopaminergic presynaptic transporters was observed in the putamen and right caudate nucleus, and FDG-PET revealed severe temporoparietal hypometabolism, with increased metabolic activity in the occipital cortex. Lastly, diffuse amyloid accumulation was observed in the cortex and basal ganglia, as assessed by PiB-PET, and in cerebrospinal fluid, Aβ42 was reduced, while total tau levels were increased and phosphorylated tau levels were unaffected.

Also of note, an analysis of the Aβ peptides in the cerebrospinal fluid of a symptomatic carrier revealed reduced Aβ38 and Aβ40 levels that were similar in magnitude suggesting proportional reductions in Aβ43 to Aβ40 production and Aβ42 to Aβ38 production, as observed for other familial AD mutations (Kakuda et al., 2021). In contrast, Aβ42 and Aβ43 levels were differentially affected, with relatively high levels of Aβ43 resulting in an elevated Aβ43/Aβ42 ratio.

Biological Effect

This mutation has been shown to increase the Aβ42/Aβ40 ratio in multiple assays. In transfected cells, the mutation was initially reported to result in a marked increase in Aβ42 production and, consequently, in the Aβ42/Aβ40 ratio (Ataka et al., 2004). A subsequent cell-based study revealed reductions in both Aβ42 and Aβ40 production (Kakuda et al., 2021), as did an in vitro assay using isolated proteins (Sun et al., 2017), but the increase in Aβ42/Aβ40 was confirmed in both cases.

Of note, the mutant was also found to increase production of the toxic Aβ43 peptide (Kakuda et al., 2021). Analyses of the short peptides generated from the stepwise processing of Aβ suggested this increase may be due to a switch in the Aβ43 production line, with Aβ43 arising from Aβ48, instead of, or in addition to, its normal Aβ49 precursor. Interestingly, an examination of multiple familial AD mutations revealed that increased Aβ43 levels, and increased production by the alternate Aβ48 pathway, correlated with younger ages at disease onset.

L85 closely contacts APP as revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment (Zhou et al., 2019; Jan 2019 news). Interestingly, the residue contributes to APP but not Notch binding (Yang et al., 2019).

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.

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References

News Citations

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

Paper Citations

1. Levine DN, Lee JM, Fisher CM. The visual variant of Alzheimer's disease: a clinicopathologic case study. Neurology. 1993 Feb;43(2):305-13. PubMed.
2. Ataka S, Tomiyama T, Takuma H, Yamashita T, Shimada H, Tsutada T, Kawabata K, Mori H, Miki T. A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis. Arch Neurol. 2004 Nov;61(11):1773-6. PubMed.
3. López-García S, Jiménez-Bonilla J, López Delgado A, Orizaola Balaguer P, Infante Ceberio J, Banzo Marraco I, Rodríguez Rodríguez E, Sánchez-Juan P. A Rare PSEN1 (Leu85Pro) Mutation Causing Alzheimer's Disease in a 29-Year-Old Woman Presenting as Corticobasal Syndrome. J Alzheimers Dis. 2019;70(3):655-658. PubMed.
4. Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
5. 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.
6. 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.
7. Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.
8. 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.

Further Reading

No Available Further Reading