Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS2, PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73219192 C>A
Position: (GRCh37/hg19):Chr14:73685900 C>A
dbSNP ID: rs121917808
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was first identified in a woman from Australia who developed forgetfulness and depression in her late 20s (Taddei et al., 1998). By age 34 she also had an abnormal gait and brisk (increased) reflexes. Genetic analysis of exons 16 and 17 of APP showed no additional mutations. Her family history is largely unknown, but her father reportedly died from a progressive neurological disease in his 40s. Segregation with disease could not be determined.

This mutation was later identified in a woman from the United Kingdom who developed a progressive parkinsonian syndrome at age 42 (Beck et al., 2004). Her symptoms also included mild spastic paraparesis and dementia. She died at age 58, after a 16-year disease course. AD was diagnosed at autopsy. Genetic screening of her peripheral lymphocytes failed to reveal mutations, but the P436Q mutation was detected in DNA isolated from her cerebral cortex, indicating mosaicism. The woman’s parents were both unaffected at the time of their deaths, one at age 73 and the other at 37, and none of her six siblings were affected by neurodegenerative disease at the time of the report. Therefore, the P436Q mutation is thought to have occurred de novo in this woman. Given that the mutation was detected in her brain, but not in lymphocytes, it is thought to have arisen during gastrulation, perhaps in the inner cell mass of the blastocyst. 

The daughter of the mutation carrier described above developed a different neurodegenerative phenotype at the age of 27. She developed a progressive cerebellar syndrome with spastic paraparesis and dementia. She died 12 years after diagnosis. No autopsy was performed. The mutation was detectable in her peripheral lymphocytes and appears to have been inherited as a germline mutation.

In addition, a Spanish man with sporadic AD whose symptoms emerged in his 20s was reported as a de novo carrier of this variant (Agüero et al., 2021). The patient had severe visual agnosia and mild limb spasticity with brisk reflexes. 

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

Neuropathology

Neuropathology consistent with AD in at least one mutation carrier, including frequent Aβ plaques, many of the cotton-wool type, and severe neurofibrillary tangle pathology (Braak and Braak stage VI) (Beck et al., 2004). Interestingly, consistent with his visual impairment, the Spanish de novo carrier had a very high burden of amyloid plaques in the posterior cortex as assessed by PET imaging (Aguero et al., 2021). Moreover, he had reduced Aβ42 levels and Aβ42/40 in cerebrospinal fluid, with increased phospho-tau, and normal total tau levels. Brain MRI and FDG-PET scans showed severe parieto-occipital atrophy and hypometabolism.

Biological Effect

In mouse embryonic fibroblasts lacking endogenous PSEN1 and PSEN2, the P436Q mutant increased the Aβ42/Aβ40 ratio, while reducing production of Aβ40, Aβ42, and APP and Notch intracellular domains compared with cells transfected with wild-type PSEN1 (Heilig et al., 2010). In addition, autoproteolytic processing of PSEN1 was substantially reduced.

Consistent with these findings, 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).

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 (Heilig et al., 2010). 

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. Taddei K, Kwok JB, Kril JJ, Halliday GM, Creasey H, Hallupp M, Fisher C, Brooks WS, Chung C, Andrews C, Masters CL, Schofield PR, Martins RN. Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998 Oct 5;9(14):3335-9. PubMed.
2. Beck JA, Poulter M, Campbell TA, Uphill JB, Adamson G, Geddes JF, Revesz T, Davis MB, Wood NW, Collinge J, Tabrizi SJ. Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease. Hum Mol Genet. 2004 Jun 15;13(12):1219-24. Epub 2004 Apr 28 PubMed.
3. Agüero P, Sainz MJ, Téllez R, Lorda I, Ávila A, García-Ribas G, Rodríguez PP, Gómez-Tortosa E. De Novo PS1 Mutation (Pro436Gln) in a Very Early-Onset Posterior Variant of Alzheimer's Disease Associated with Spasticity: A Case Report. J Alzheimers Dis. 2021;83(3):1011-1016. PubMed.
4. Bagaria J, Bagyinszky E, An SS. Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene. Int J Mol Sci. 2022 Sep 19;23(18) PubMed.
5. 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.
6. 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.
7. 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.

Further Reading