Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic, Spastic Paraparesis : Not Classified, Cerebral Amyloid Angiopathy : Not Classified
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73664750 G>T
dbSNP ID: rs63750964
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a kindred in which affected members had both spasticity and dementia (Farlow et al., 2000). The proband first developed progressive stiffening in his legs at age 38 and subsequently suffered from impaired short-term memory, ability to do calculations, and executive function at age 42. At this stage, brain MRI, visual evoked potentials, and lower extremity nerve conduction were normal. Across a span of three years, the proband became wheelchair-bound and deeply demented. His father, sister, and a paternal aunt developed similar symptoms and died in their 40s. The proband and two affected siblings were shown to carry the mutation which was absent from 120 normal controls.

The mutation was also found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the U.S., Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD.

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

Neuropathology
Neuropathology was consistent with AD and included cotton-wool plaques and severe cerebral amyloid angiopathy involving the leptomeninges, cerebral, and cerebellar parenchyma (Farlow et al., 2000; Albrecht et al., 2009). In addition, degeneration of the lateral pyramidal tracts was seen in the spinal cord.

Biological Effect
In vitro experiments using the APP C99 substrate, showed the mutant protein produced less Aβ42 and Aβ40 than wild-type PSEN1, and increased the Aβ42/Aβ40 ratio approximately five-fold (Bai et al., 2015; Sun et al., 2017). In addition, the mutant nearly abrogated autoproteolysis. Subsequent experiments in HEK293 cells stably overexpressing Swedish (sw) mutant APP in combination with the mutant protein, revealed a very large relative increase in Aβ43 production (Trambauer et al., 2020). The interaction of the mutant with the Aβ peptide precursor C99 was disrupted as assessed by cross-linking experiments. V261 is proximal to the PSEN1 active site and the authors suggest this altered positioning likely interferes with normal ε‐site cleavage and affects Aβ substrate–γ‐secretase interactions whose strength play a key role in the carboxy‐terminal trimming pathway and the generation of pathogenic longer Aβ species.

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). These authors classified the variant as pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

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References

Paper Citations

1. Farlow MR, Murrell JR, Hulette CM, Ghetti B. Hereditary lateral sclerosis and Alzheimer disease associated with mutation at codon 261 of the presenilin 1 (PS1) gene. Neurobiol Aging. 2000 May-Jun; 21(Suppl 1):62.
2. 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.
3. Albrecht S, Bogdanovic N, Ghetti B, Winblad B, Leblanc AC. Caspase-6 activation in familial alzheimer disease brains carrying amyloid precursor protein or presenilin i or presenilin II mutations. J Neuropathol Exp Neurol. 2009 Dec;68(12):1282-93. PubMed.
4. Bai XC, Yan C, Yang G, Lu P, Ma D, Sun L, Zhou R, Scheres SH, Shi Y. An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 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. Trambauer J, Rodríguez Sarmiento RM, Fukumori A, Feederle R, Baumann K, Steiner H. Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation. EMBO Rep. 2020 Jan 7;21(1):e47996. Epub 2019 Nov 25 PubMed.
7. 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.
8. 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.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading