Mutations

PSEN1 A431E

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Spastic Paraparesis : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73219177 C>A
Position: (GRCh37/hg19):Chr14:73685885 C>A
dbSNP ID: rs63750083
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCA to GAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

First identified in a genetic screen of individuals with early onset familial Alzheimer’s disease (Rogaeva et al., 2001), this mutation was subsequently found in numerous families with ancestry tracing to the state of Jalisco in Western Mexico. It is suspected to be one of the most common AD mutations in people of Mexican heritage.

Indeed, a study of 13 Mexican families affected by autosomal-dominant AD, revealed that nine carried the A431E mutation. Within these nine families, 13 individuals were clinically diagnosed with AD. The disease was transmitted in an autosomal-dominant manner. Haplotype analysis suggested that these individuals share a common ancestor, demonstrating a founder effect (Yescas et al., 2006).

An additional 20 patients from 15 putatively unrelated families were also reported to carry the A431E mutation (Murrell et al., 2006). The 15 families were from Guadalajara (two), Chicago (one), and Southern California (12). All but one of the families could trace their ancestry to Jalisco. The remaining A431E proband was from Arizona and identified as non-Hispanic Caucasian. Haplotype analysis showed that all A431E mutation carriers in this study descended from a common ancestor.

More recently, 46 index cases from Jalisco with 301 affected relatives and 560 descendants, each with a 50 percent chance of carrying the mutation, were reported in the largest study of the mutation to date (Dumois-Petersen et al., 2020). Consistent with previous reports, the average age of onset in the probands was 42.5 years and mean disease duration was 7.5 years. This study also confirmed that substantial clinical heterogeneity characterizes disease presentation in A431E carriers. 

Cognitive changes usually include memory loss and language impariment (Yescas et al., 2006; Murrell et al., 2006; Dumois-Petersen et al., 2020), with subtle deficits possibly arising before disease onset (Medina et al., 2021). However, motor symptoms, such as spastic paraplegia, myoclonus, Parkinsonism, and pyramidal rigidity, are also common, with 92 percent of carriers showing gait abnormalities, 77 percent developing spasticity in the first two years of disease, 28 percent suffering from Parkinsonism, and 15 percent experiencing seizures (Dumois-Petersen et al., 2020). At least one proband had a history of partial seizures 20 years before the onset of AD symptoms (Yescas et al., 2006; Murrell et al., 2006). Also, cerebellar dysfunction was reported in 23 percent of carriers (Dumois-Petersen et al., 2020). Interestingly, in one family, affected members spanning four generations had initial motor symptoms with subsequent mild, atypical cognitive impairment, or in some cases, no apparent cognitive alterations at all (Santos-Mandujano et al., 2019).

Psychological changes, and especially depression, are common and may occur early in mutation carriers. More than half of the carriers examined by Dumois-Petersen and colleagues suffered from depression (Dumois-Petersen et al., 2020).  Moreover, in a study of 33 young Mexican women (average age about 31), mutation carriers (who were unaware of mutation status) were likelier to exhibit symptoms of depression than non-mutation carriers, and twice as likely to have sought psychiatric help (Ringman et al., 2004). Also, 30 percent of carriers in the large study had delusions and 11 percent experienced hallucinations (Dumois-Petersen et al., 2020). In one case, a 35-year-old carrier presented with mutism, lack of spontaneous movement, and refusal to eat, resulting in a presumptive diagnosis of catatonia (Alakkas et al., 2020).

Homozygosity for this mutation was reported in a 35- year-old man with childhood learning disability and onset of progressive cognitive deficits leading to dementia at age 33 (Parker et al., 2019). The patient suffered from chronic nighttime behavioral disturbance, possibly REM behavior disorder, as well as spastic paraparesis and pseudobulbar affect, a condition characterized by episodes of sudden uncontrollable laughing or crying.

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

The published literature on this mutation has been compiled in a review (Orozco-Barajas et al., 2022).

Neuropathology

At least five autopsied cases confirmed the diagnosis of AD (Murrell et al., 2006). Brain imaging showed mutation carriers were affected by cortical and subcortical atrophy (Yescas et al., 2006). In one case, cotton-wool plaques were reported as the most abundant type of Aβ deposit, present throughout cortical layers, but particularly abundant in the upper layers (Maarouf et al., 2008). Mature, cored neuritic plaques were frequently observed, while primitive plaques were scarce. Also of note, levels of Aβ40 in the cortex were high compared with those in carriers of other PSEN mutations, and the Aβ42/Aβ40 ratio was less than 1. Moreover, neurofilament tangles and tau dimers were very abundant.

In several mutation carriers, white matter abnormalities have been reported. In three carriers of the mutation with spastic paraparesis, widespread white-matter abnormalities were observed in the corpus callosum, occipital, parietal, and frontal lobes (Soosman et al., 2016). Consistent with this alteration, in one of the individuals, electrophysiological measurements revealed slowed motor and sensory conduction in the lower extremities. PiB-PET imaging, however, showed low amyloid burden in sensorimotor cortex. Moreover, three mutation carriers from another family, including one symptomatic, one presymptomatic, and one asymptomatic individual, had periventricular white-matter hyperintensities suggestive of early glial and vascular pathology that seemed to be consistent with the individuals’ clinical stage of disease and cortical atrophy pattern (Santos-Mandujano et al., 2019). An imaging study of carriers of a number of AD-associated mutations revealed that A431E carriers had an unusually high incidence of cerebral microhemorrhages (Joseph-Mathurin et al., 2021).

In the homozygous individual, MRI revealed a high level of cerebral atrophy. Also, chronic microhemorrhages were seen in occipital, temporal, and right frontal lobes (Parker et al., 2019).

Of note, one carrier was reported to have Lewy body pathology, as assessed by α-synuclein staining, in the amygdala, cingulate gyrus, and neocortex (Leverenz et al., 2020). However, no detectable staining was observed in another carrier from the same family, with the same age at onset (51) and similar disease duration (10 versus 9 years). 

The mutation has been associated with increased levels of Aβ42 in the plasma of presymptomatic individuals, and in cerebrospinal fluid, with a decline in Aβ42 levels and a reduced Aβ42/Aβ40 ratio (Ringman et al., 2008; Ringman et al., 2012). Further biomarker analysis revealed mutation carriers have lower CSF levels of Aβ37, Aβ38, and Aβ39, suggesting a disruption of γ-secretase cleavage (Portelius et al., 2010), a proposal that was subsequently verified experimentally (see below).

Biological Effect

This variant was found to substantially increase levels of toxic Aβ43 and decrease the Aβ (37 + 38 + 40) / (42 + 43) ratio in mouse embryonic fibroblasts expressing A431E on a PSEN null background and transduced with human APP-C99 (Apr 2022 news; Petit et al., 2022).  Based on analyses of multiple PSEN mutants, this ratio was reported to outperform the Aβ42/Aβ40 ratio as an indicator of AD pathogenicity and correlated with AD age at onset. In vitro experiments using APP-C99 as a substrate indicated the mutation increases the Aβ42/Aβ40 ratio, while reducing production of both Aβ40 and Aβ42 (Sun et al., 2017). Of note, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that A431 is apposed to the β-strand of APP which forms part of a hybrid, three-stranded β–sheet required for cleavage (Zhou et al., 2019; Jan 2019 news).

The A431E mutation may also affect cellular functions beyond APP processing. For example, it may alter monoamine oxidase-A (MAO-A) activity, as suggested by the enhanced MAO-A activity observed in hippocampal HT-22 cells expressing PSEN1 A431E (Pennington et al., 2011). This effect could help explain the frequently observed depression in patients carrying the mutation. A431E has also been reported to increase the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), induce oxidative stress, and disrupt mitochondrial function (Han et al., 2021).

Moreover, neurons differentiated from patient induced pluripotent stem cells, revealed a surprising increase in the expression of cell cycle genes together with activation of REST, a neural repressor that regulates neuronal differentiation (Caldwell et al., 2020) and which has been implicated in neurodegenerative disease (Hwang and Zukin, 2018). Genes involved in inflammation and non-neuronal differentiation pathways, including Notch and TGF-β, were also upregulated. Corresponding changes in in histone methylation and chromatin topology were reported.

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Yescas et al., 2006, 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-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. A431E: Cryo-EM data suggest residue is of 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.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. A431E: At least one family with >=3 affected carriers and >=1 unaffected noncarriers, and cosegregation demonstrated in >1 family.

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)

Research Models

A neuronal cell model has been generated directly from adult fibroblasts isolated from a 46-year-old male carrier (Chou et al., 2023, Jun 2023 news). Unlike neurons differentiatd from induced pluripotent stem cells, these transdifferentiated neurons, called tNeurons, retain epigenetic marks of aging.

Last Updated: 25 Mar 2024

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References

News Citations

  1. Better Cell Model? Transdifferentiated Neurons Capture AD-Like Changes
  2. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  3. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. Chou C-C, Vest R, Prado MA, Wilson-Grady J, Paulo JA, Shibuya Y, Moran-Losada P, Lee T-T, Luo J, Gygi SP, Kelly JW, Finley D, Wernig M, Wyss-Coray T, Frydman J. Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons. 2023 Mar 27 10.1101/2023.03.27.534444 (version 1) bioRxiv.
  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. Yescas P, Huertas-Vazquez A, Villarreal-Molina MT, Rasmussen A, Tusié-Luna MT, López M, Canizales-Quinteros S, Alonso ME. Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families. Neurogenetics. 2006 Jul;7(3):195-200. Epub 2006 Apr 21 PubMed.
  4. Murrell J, Ghetti B, Cochran E, Macias-Islas MA, Medina L, Varpetian A, Cummings JL, Mendez MF, Kawas C, Chui H, Ringman JM. The A431E mutation in PSEN1 causing familial Alzheimer's disease originating in Jalisco State, Mexico: an additional fifteen families. Neurogenetics. 2006 Nov;7(4):277-9. Epub 2006 Aug 5 PubMed.
  5. Dumois-Petersen S, Gallegos-Arreola MP, Magaña-Torres MT, Perea-Díaz FJ, Ringman JM, Figuera LE. Autosomal dominant early onset Alzheimer's disease in the Mexican state of Jalisco: High frequency of the mutation PSEN1 c.1292C>A and phenotypic profile of patients. Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):1023-1029. Epub 2020 Dec 4 PubMed.
  6. Medina LD, Woo E, Rodriguez-Agudelo Y, Chaparro Maldonado H, Yi D, Coppola G, Zhou Y, Chui HC, Ringman JM. Reaction time and response inhibition in autosomal dominant Alzheimer's disease. Brain Cogn. 2021 Feb;147:105656. Epub 2020 Dec 10 PubMed.
  7. Santos-Mandujano RA, Ryan NS, Chávez-Gutiérrez L, Sánchez-Torres C, Meraz-Ríos MA. Clinical Association of White Matter Hyperintensities Localization in a Mexican Family with Spastic Paraparesis Carrying the PSEN1 A431E Mutation. J Alzheimers Dis. 2020;73(3):1075-1083. PubMed.
  8. Ringman JM, Diaz-Olavarrieta C, Rodriguez Y, Chavez M, Paz F, Murrell J, Macias MA, Hill M, Kawas C. Female preclinical presenilin-1 mutation carriers unaware of their genetic status have higher levels of depression than their non-mutation carrying kin. J Neurol Neurosurg Psychiatry. 2004 Mar;75(3):500-2. PubMed.
  9. Alakkas A, Meyer A, Debbold E, Yagudayeva R, Bui J. Early-Onset Alzheimer's Disease Masquerading as Catatonia. Case Rep Neurol Med. 2020;2020:1493481. Epub 2020 Sep 12 PubMed.
  10. Parker J, Mozaffar T, Messmore A, Deignan JL, Kimonis VE, Ringman JM. Homozygosity for the A431E mutation in PSEN1 presenting with a relatively aggressive phenotype. Neurosci Lett. 2019 Apr 23;699:195-198. Epub 2019 Feb 1 PubMed.
  11. Orozco-Barajas M, Oropeza-Ruvalcaba Y, Canales-Aguirre AA, Sánchez-González VJ. PSEN1 c.1292C. Front Aging Neurosci. 2022;14:860529. Epub 2022 Jul 22 PubMed.
  12. Maarouf CL, Daugs ID, Spina S, Vidal R, Kokjohn TA, Patton RL, Kalback WM, Luehrs DC, Walker DG, Castaño EM, Beach TG, Ghetti B, Roher AE. Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. Mol Neurodegener. 2008 Nov 20;3:20. PubMed.
  13. Soosman SK, Joseph-Mathurin N, Braskie MN, Bordelon YM, Wharton D, Casado M, Coppola G, McCallum H, Nuwer M, Coutin-Churchman P, Apostolova LG, Benzinger T, Ringman JM. Widespread white matter and conduction defects in PSEN1-related spastic paraparesis. Neurobiol Aging. 2016 Nov;47:201-209. Epub 2016 Aug 8 PubMed.
  14. Joseph-Mathurin N, Wang G, Kantarci K, Jack CR Jr, McDade E, Hassenstab J, Blazey TM, Gordon BA, Su Y, Chen G, Massoumzadeh P, Hornbeck RC, Allegri RF, Ances BM, Berman SB, Brickman AM, Brooks WS, Cash DM, Chhatwal JP, Chui HC, Correia S, Cruchaga C, Farlow MR, Fox NC, Fulham M, Ghetti B, Graff-Radford NR, Johnson KA, Karch CM, Laske C, Lee AK, Levin J, Masters CL, Noble JM, O'Connor A, Perrin RJ, Preboske GM, Ringman JM, Rowe CC, Salloway S, Saykin AJ, Schofield PR, Shimada H, Shoji M, Suzuki K, Villemagne VL, Xiong C, Yakushev I, Morris JC, Bateman RJ, Benzinger TL, Dominantly Inherited Alzheimer Network. Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease. Neurology. 2021 Mar 23;96(12):e1632-e1645. Epub 2021 Jan 25 PubMed.
  15. Leverenz JB, Fishel MA, Peskind ER, Montine TJ, Nochlin D, Steinbart E, Raskind MA, Schellenberg GD, Bird TD, Tsuang D. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
  16. Ringman JM, Younkin SG, Pratico D, Seltzer W, Cole GM, Geschwind DH, Rodriguez-Agudelo Y, Schaffer B, Fein J, Sokolow S, Rosario ER, Gylys KH, Varpetian A, Medina LD, Cummings JL. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology. 2008 Jul 8;71(2):85-92. PubMed.
  17. Ringman JM, Coppola G, Elashoff D, Rodriguez-Agudelo Y, Medina LD, Gylys K, Cummings JL, Cole GM. Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer's disease. Dement Geriatr Cogn Disord. 2012;33(1):1-5. PubMed.
  18. Portelius E, Andreasson U, Ringman JM, Buerger K, Daborg J, Buchhave P, Hansson O, Harmsen A, Gustavsson MK, Hanse E, Galasko D, Hampel H, Blennow K, Zetterberg H. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease. Mol Neurodegener. 2010;5:2. PubMed.
  19. 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.
  20. 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.
  21. 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.
  22. Pennington PR, Wei Z, Rui L, Doig JA, Graham B, Kuski K, Gabriel GG, Mousseau DD. Alzheimer disease-related presenilin-1 variants exert distinct effects on monoamine oxidase-A activity in vitro. J Neural Transm. 2011 Jul;118(7):987-95. PubMed.
  23. Han J, Park H, Maharana C, Gwon AR, Park J, Baek SH, Bae HG, Cho Y, Kim HK, Sul JH, Lee J, Kim E, Kim J, Cho Y, Park S, Palomera LF, Arumugam TV, Mattson MP, Jo DG. Alzheimer's disease-causing presenilin-1 mutations have deleterious effects on mitochondrial function. Theranostics. 2021;11(18):8855-8873. Epub 2021 Aug 17 PubMed.
  24. Caldwell AB, Liu Q, Schroth GP, Galasko DR, Yuan SH, Wagner SL, Subramaniam S. Dedifferentiation and neuronal repression define familial Alzheimer's disease. Sci Adv. 2020 Nov;6(46) Print 2020 Nov PubMed.
  25. Hwang JY, Zukin RS. REST, a master transcriptional regulator in neurodegenerative disease. Curr Opin Neurobiol. 2018 Feb;48:193-200. Epub 2018 Jan 30 PubMed.
  26. 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

Papers

  1. Ringman JM, Medina LD, Rodriguez-Agudelo Y, Chavez M, Lu P, Cummings JL. Current concepts of mild cognitive impairment and their applicability to persons at-risk for familial Alzheimer's disease. Curr Alzheimer Res. 2009 Aug;6(4):341-6. PubMed.
  2. Lee P, Medina L, Ringman JM. The Thr354Ile substitution in PSEN1:: disease-causing mutation or polymorphism?. Neurology. 2006 Jun 27;66(12):1955-6. PubMed.
  3. Llibre-Guerra JJ, Li Y, Allegri RF, Mendez PC, Surace EI, Llibre-Rodriguez JJ, Sosa AL, Aláez-Verson C, Longoria EM, Tellez A, Carrillo-Sánchez K, Flores-Lagunes LL, Sánchez V, Takada LT, Nitrini R, Ferreira-Frota NA, Benevides-Lima J, Lopera F, Ramírez L, Jiménez-Velázquez I, Schenk C, Acosta D, Behrens MI, Doering M, Ziegemeier E, Morris JC, McDade E, Bateman RJ. Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes. Alzheimers Dement. 2021 Apr;17(4):653-664. Epub 2020 Nov 23 PubMed.
  4. Singer MB, Ringman JM, Chu Z, Zhou X, Jiang X, Shahidzadeh A, Wang RK, Kashani AH. Abnormal retinal capillary blood flow in autosomal dominant Alzheimer's disease. Alzheimers Dement (Amst). 2021;13(1):e12162. Epub 2021 Mar 4 PubMed.
  5. Reyes-Domínguez YA, Figuera LE, Brambila-Tapia AJ. Perceptions of Knowledge, Disease Impact and Predictive Genetic Testing in Family Members at Risk to Develop Early-Onset Alzheimer's Disease (EOAD) and Their Levels of Suicidal Ideation: A Mixed Study. Brain Sci. 2023 Mar 16;13(3) PubMed.
  6. Klingstedt T, Lantz L, Shirani H, Ge J, Hanrieder J, Vidal R, Ghetti B, Nilsson KP. Thiophene-Based Ligands for Specific Assignment of Distinct Aβ Pathologies in Alzheimer's Disease. ACS Chem Neurosci. 2024 Apr 3;15(7):1581-1595. Epub 2024 Mar 24 PubMed.

Protein Diagram

Primary Papers

  1. 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.
  2. Yescas P, Huertas-Vazquez A, Villarreal-Molina MT, Rasmussen A, Tusié-Luna MT, López M, Canizales-Quinteros S, Alonso ME. Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families. Neurogenetics. 2006 Jul;7(3):195-200. Epub 2006 Apr 21 PubMed.

Other mutations at this position

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