Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS2, PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659500 A>G
dbSNP ID: rs63751287
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation has been associated with a complex and severe set of clinical phenotypes that present at a very young age and include, not only cognitive impairments typical of Alzheimer's disease, but motor, cerebellar, and psychiatric disturbances as well. It has been detected in individuals and families from various countries worldwide.

The mutation was first reported in an American study that described a woman with very early onset Alzheimer’s disease (at age 28) whose pedigree showed five affected family members over four generations (Houlden et al., 2001). Disease in the proband progressed rapidly, and she died at age 34. Her clinical presentation involved extrapyramidal features and early seizures. The clinical course in the proband was typical of her family, with affected members experiencing onset between the ages of 28 and 34 years, followed by rapid deterioration leading to death between 34 and 37. The clinical and neuropathological characteristics of this pedigree were described prior to the identification of the mutation (Revesz et al., 1997). Although lack of DNA from family members precluded segregation analysis, the inheritance pattern was consistent with an autosomal-dominant trait. The mutation was not present in 150 control chromosomes.

Subsequently, the mutation was found in three members of a Canadian-Vietnamese family, who displayed a variety of atypical motor and psychiatric symptoms (Appel-Cresswell et al., 2018). The proband had a history of drug abuse in her teens. In her 20s, she exhibited memory and cognitive dysfunction, ataxia, dystonia, and verbal aggression, and experienced auditory hallucinations and seizures. By age 30, she was dysphagic, immobile, incontinent, and mute. An MRI at age 28 revealed generalized cerebral atrophy. The proband’s brother and father each began exhibiting symptoms at age 15—unsteady gait and cognitive difficulties in the former, and hallucinations in the latter—and by their 30s, they too displayed ataxia, dementia, neuropsychiatric symptoms, and evidence of seizures. The mother of the two affected siblings was neurologically normal and did not carry the M233V mutation, indicating segregation with disease.

The mutation was also identified in a Chinese individual who experienced memory loss starting at age 25, followed by bilateral parkinsonism responsive to L-DOPA at age 28 (Liu et al., 2019). The patient had two tonic-clonic seizures as a child. The mutation appears to have arisen de novo, as the parents did not carry the mutation.

Interestingly, the mutation was also found in a man of Azerbaijani origin whose initial symptoms, starting at age 18, resembled spinocerebellar ataxia, including progressive impairment of coordination followed by memory loss (Seliverstov et al., 2020). Autosomal dominant inheritance was suggested given that a similar condition afflicted three of the man's family members, his mother, maternal grandfather, and maternal great-aunt, all of whom died by age 40. Because no mutations in SCA genes 1, 2, 3, 6, and 17 were identified in the proband, the authors screened a gene panel including 723 genes associated with neurodegenerative disease leading to the identification of the M233V mutation. 

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

Neuropathology

Neuropathological examination of the proband of the first family showed abundant neurofibrillary tangles and amyloid plaques throughout the cerebral cortex. Occasional plaques in the spinal cord were also noted. Lewy bodies were observed in the substantia nigra and cortex. Moderate to severe amyloid angiopathy was also present in leptomeningeal, cerebral, and cerebellar vessels (Revesz et al., 1997; Houlden et al., 2001).

A multimodal imaging study of a 31-year-old German carrier suffering from progressive memory and motor impairments revealed widespread β-amyloid deposits in cortical regions and the striatum, as well as tau pathology in mesial-temporal areas (Aghakhanyan et al., 2021). Also, the authors detected atrophy of the hippocampus and amygdala, with cortical thinning in the right middle temporal lobe. White matter alterations were also noted, as were disruptions in the default mode network and in sensory-motor connectivity. 

In the Chinese patient, FDG-PET revealed mild, bilateral hypermetabolism in the posterior putamen three years after onset, and hypometabolism in the posterior parietal cortex and right medial temporal lobe five years after onset (Liu et al., 2019). In addition, PiB-PET and florbetapir-PET indicated amyloid deposition in the frontal lobe, posterior cingulate, caudate, putament, and thalamus, and DAT-PET suggested reduced levels of dopamine transporters in the left putamen three years after onset. 

The man of Azerbaijani origin had bilateral hippocampal atrophy and mild atrophy of the left temporoparietal cortex as assessed by MRI (Seliverstov et al., 2020).

Biological Effect

When transfected into HEK293 cells stably expressing Swedish mtAPP 695 and BACE1, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1. This resulted in reduced secreted Aβ40, increased Aβ42, and an increased Aβ42/Aβ40 ratio (Li et al., 2016). Moreover, subsequent cell-based studies that surveyed Aβ production in greater detail 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).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicated that, in wild-type PSEN1, this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

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. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Houlden H, Crook R, Dolan RJ, McLaughlin J, Revesz T, Hardy J. A novel presenilin mutation (M233V) causing very early onset Alzheimer's disease with Lewy bodies. Neurosci Lett. 2001 Nov 2;313(1-2):93-5. PubMed.
2. Revesz T, McLaughlin JL, Rossor MN, Lantos PL. Pathology of familial Alzheimer's disease with Lewy bodies. J Neural Transm Suppl. 1997;51:121-35. PubMed.
3. Appel-Cresswell S, Guella I, Lehman A, Foti D, Farrer MJ. PSEN1 p.Met233Val in a Complex Neurodegenerative Movement and Neuropsychiatric Disorder. J Mov Disord. 2018 Jan;11(1):45-48. Epub 2018 Jan 11 PubMed.
4. Liu J, Wang Q, Jing D, Gao R, Zhang J, Cui C, Qiao H, Liang Z, Wang C, Rosa-Neto P, Wu L, Jia J, Gauthier S. Diagnostic Approach of Early-Onset Dementia with Negative Family History: Implications from Two Cases of Early-Onset Alzheimer's Disease with De Novo PSEN1 Mutation. J Alzheimers Dis. 2019;68(2):551-558. PubMed.
5. Seliverstov Y, Kanivets I, Illarioshkin S. Spinocerebellar Ataxia-Like Presentation of the M233V PSEN1 Mutation. Cerebellum. 2020 Oct;19(5):744-747. PubMed.
6. Aghakhanyan G, Saur D, Rullmann M, Weise CM, Schroeter ML, Marek K, Jamra RA, Tiepolt S, Strauss M, Scherlach C, Hoffmann KT, Sabri O, Classen J, Barthel H. PET/MRI Delivers Multimodal Brain Signature in Alzheimer's Disease with De Novo PSEN1 Mutation. Curr Alzheimer Res. 2021;18(2):178-184. PubMed.
7. Li N, Liu K, Qiu Y, Ren Z, Dai R, Deng Y, Qing H. Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
8. 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.
9. 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.
10. 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.
11. 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