Mutations

PSEN1 A431E (Jalisco)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73685885 C>A
dbSNP ID: rs63750083
Coding/Non-Coding: Coding
Genomic Region: Exon 12
Mutation Type: Point, Missense
Codon Change: GCA to GAA

Findings

This mutation was first published in five individuals with Alzheimer’s disease in a large genetic screen. Clinical details and family history information were not reported (Rogaeva et al., 2001).

This mutation was found in numerous families with ancestry tracing to the state of Jalisco in Western Mexico and may be one of the most prominent AD mutations in people with Mexican heritage. Of 13 Mexican families affected by autosomal dominant AD, nine were shown to carry 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 (2), Chicago (1), 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.

This mutation was also identified in a 46-year old-man clinically diagnosed with AD who had a family history consistent with AD. His father was from Jalisco and had died at the age of 32 from an accident. This proband is unusual in that he also carried a second missense mutation in presenilin-1, T354I. It is likely that the Jalisco mutation accounts for the disease in this individual; however, the significance of the T354I mutation is unclear and may be benign (Lee et al., 2006).

The average age of onset in these families was about 40 years of age, ranging from about 33 to 44. In addition to cognitive changes, especially memory problems, some individuals showed prominent depression and personality changes. Motor symptoms, such as spastic paraplegia, myoclonus, and pyramidal rigidity, were also noted among some. 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). Psychological changes, and especially depression, may occur early in mutation carriers. In a study of 33 young Mexican woman (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).

This mutation is associated with increased levels of Aβ1-42 in the plasma of presymptomatic individuals. In the cerebrospinal fluid, it is associated with a decline in Aβ42 levels and a reduced Aβ42/40 ratio (Ringman et al., 2008; Ringman et al., 2012). Further biomarker analysis suggested A431E mutation carriers may have lower CSF levels of Aβ1-37, Aβ1-38, and Aβ1-39, suggesting the mutation may modulate γ-secretase cleavage (Portelius et al., 2010).

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).

Biological Effect

Unknown. In silico analysis predicts a possibly damaging effect of the mutation (Yescas et al., 2006).

Comments

Comments on this content

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

  1. PSEN1 T354I

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. . The Thr354Ile substitution in PSEN1:: disease-causing mutation or polymorphism?. Neurology. 2006 Jun 27;66(12):1955-6. PubMed.
  5. . 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.
  6. . Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology. 2008 Jul 8;71(2):85-92. PubMed.
  7. . Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer's disease. Dement Geriatr Cogn Disord. 2012;33(1):1-5. PubMed.
  8. . Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease. Mol Neurodegener. 2010;5:2. PubMed.

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.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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.

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.

Alzpedia