Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73685899 C>T
dbSNP ID: rs63749925
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to TCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in two affected siblings from a family in the UK with members who had been diagnosed with probable or definite AD across two or more generations (Palmer et al., 1999). Disease onset occurred at 50 and 44 years of age. The mutation was absent from 92 controls.

A subsequent study of the same kindred identified an autosomal dominant pattern of inheritance including eight affected individuals, spanning three generations (Arber et al., 2024). Also, two additional affected carriers were reported: the child of the proband and a nephew/niece. The average age at onset was 46 years, ranging from 44 to 50 years. In most cases (4 of 5), the initial symptom was memory loss with apraxia emerging shortly after. However, in one case, atypical executive dysfunction emerged first. In the later stages of disease, lower limb pyramidal signs or spastic paraparesis were observed in three of five individuals with documented neurological examinations. Clinical phenotype heterogeneity was also reflected in a wide range of disease durations (5-21 years) and ages at death (49-68 years).

This variant was absent from the gnomAD variant database (gnomAD v4.1.0, Jun 2024).

Neuropathology
In the proband, neuropathology was consistent with severe AD and severe cerebral amyloid angiopathy (CAA) (Arber et al., 2024). Both cotton wool and dense-core amyloid plaques were observed. In addition, Lewy body pathology was identified, predominantly in the amygdala. Of note, immunohistochemical analysis of the temporal cortex indicated Aβ43 is a major component of the dense cores of amyloid plaques and is abundant in vessels with CAA.

MRI brain scans of two other carriers revealed generalized atrophy. In one case, the hippocampus was particularly affected, while in the other, atrophy was most prominent in posterior regions, similar to that described for posterior cortical atrophy (PCA). This latter carrier suffered from non-episodic memory impairment as a leading symptom. FLAIR and SWI imaging showed no signs of white matter hyperintensities in either carrier.

Biological Effect

In neurons derived from induced pluripotent stem cells (iPSCs) from two P436S carriers, autoproteolytic processing of PSEN1 was seemingly unaffected, but all Aβ peptides measured were increased, as were the ratios of Aβ42/Aβ40, and especially Aβ43/Aβ40 (Arber et al., 2024). Interestingly, in contrast to other PSEN1 mutations, P436S did not appear to affect the Aβ42/Aβ38, a ratio sometimes used as an indicator of γ-secretase processivity.

Consistent with some of these findings, earlier studies using P436S-transfected mouse embryonic fibroblasts (Heilig et al., 2010; Shen et al., 2019), and an in vitro assay using purified proteins (Sun et al., 2017), revealed increases in the Aβ42/Aβ40 ratio. In addition, one of the cell-based studies showed normal autoproteolytic processing and increased Aβ40, Aβ42, and Aβ43 production (Shen et al., 2019). However, Heilig and colleagues reported their transfected fibroblasts, which lacked endogenous PSEN1 and PSEN2, produced less Aβ40, Aβ42, and APP and Notch intracellular domains compared with cells transfected with wild-type PSEN1 (Heilig et al., 2010), and Sun and co-workers reported less Aβ40 production and similar levels of Aβ42 compared with wildtype PSEN1 (Sun et al., 2017).

P436 is adjacent to the PAL motif (P433, A434, L435) which is conserved across presenilins and has been implicated in the recognition of APP by γ-secretase (Sato et al., 2008; Zhou et al., 2019; Jan 2019 news). Some researchers include P436 in the motif and refer to it as PALP (e.g., Heilig et al., 2010). Proline residues are often structurally important, providing rigidity and enabling peptide turns.

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.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. P436S: Variant is in a region that is both a mutational hot spot and of likely functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 03 Jun 2024

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References

News Citations

Paper Citations

Palmer MS, Beck JA, Campbell TA, Humphries CB, Roques PK, Fox NC, Harvey R, Rossor MN, Collinge J. Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. Hum Mutat. 1999;13(3):256. PubMed.
Arber C, Belder CR, Tomczuk F, Gabriele R, Buhidma Y, Farrell C, O'Connor A, Rice H, Lashley T, Fox NC, Ryan NS, Wray S. The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations. Alzheimers Dement. 2024 Jul;20(7):4717-4726. Epub 2024 Jun 2 PubMed.
Heilig EA, Xia W, Shen J, Kelleher RJ. A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem. 2010 Jul 16;285(29):22350-9. PubMed.
Shen L, Qin W, Wu L, Zhou A, Tang Y, Wang Q, Jia L, Jia J. Two novel presenilin-1 mutations (I249L and P433S) in early onset Chinese Alzheimer's pedigrees and their functional characterization. Biochem Biophys Res Commun. 2019 Aug 13;516(1):264-269. Epub 2019 Jun 21 PubMed.
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.
Sato C, Takagi S, Tomita T, Iwatsubo T. The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase. J Neurosci. 2008 Jun 11;28(24):6264-71. PubMed.
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.
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.

Mutations

PSEN1 P436S

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