Mutations

PSEN1 A431E

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Spastic Paraparesis : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685885 C>A
dbSNP ID: rs63750083
Coding/Non-Coding: Coding
Mutation Type: Point, 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 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).

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 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). 

Biological Effect

This mutation is associated with increased levels of Aβ42 in the plasma of presymptomatic individuals. In the cerebrospinal fluid, it is associated with a decline in Aβ42 levels and a reduced Aβ42/Aβ40 ratio (Ringman et al., 2008; Ringman et al., 2012). Further biomarker analysis suggested A431E mutation carriers may have lower CSF levels of Aβ37, Aβ38, and Aβ39, suggesting the mutation may modulate γ-secretase cleavage (Portelius et al., 2010). In vitro experiments using APP-C99 as a substrate indicated the mutation reduces both Aβ40 and Aβ42 production, but the effect is stronger for Aβ40 (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 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.

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).

Last Updated: 06 Aug 2021

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . 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. . 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.
  3. . 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.
  4. . 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.
  5. . Reaction time and response inhibition in autosomal dominant Alzheimer's disease. Brain Cogn. 2021 Feb;147:105656. Epub 2020 Dec 10 PubMed.
  6. . 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.
  7. . 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.
  8. . Early-Onset Alzheimer's Disease Masquerading as Catatonia. Case Rep Neurol Med. 2020;2020:1493481. Epub 2020 Sep 12 PubMed.
  9. . 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.
  10. . Widespread white matter and conduction defects in PSEN1-related spastic paraparesis. Neurobiol Aging. 2016 Nov;47:201-209. Epub 2016 Aug 8 PubMed.
  11. . Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease. Neurology. 2021 Mar 23;96(12):e1632-e1645. Epub 2021 Jan 25 PubMed.
  12. . Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
  13. . Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology. 2008 Jul 8;71(2):85-92. PubMed.
  14. . Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer's disease. Dement Geriatr Cogn Disord. 2012;33(1):1-5. PubMed.
  15. . Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease. Mol Neurodegener. 2010;5:2. PubMed.
  16. . 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.
  17. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  18. . 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.
  19. . 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. . 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. . The Thr354Ile substitution in PSEN1:: disease-causing mutation or polymorphism?. Neurology. 2006 Jun 27;66(12):1955-6. PubMed.
  3. . 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.

Protein Diagram

Primary Papers

  1. . 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. . 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

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.