Mutations

PSEN1 E280A (Paisa)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.50024A>C
Genomic Mutation Name (NT1): g.66630A>C
dbSNP ID: rs63750231
Coding/Non-Coding: Coding
Genomic Region: Exon 8
Mutation Type: Point, Missense
Codon Change: GAA to GCA

Findings

First documented about 20 years ago, the E280A mutation is by far the most common cause of familial early onset Alzheimer’s disease, affecting hundreds of people. The majority of E280A carriers belong to a large kindred from the Colombian state of Antioquia. In fact, the mutation is often called the Paisa mutation in reference to the people of this region. The Colombian kindred is remarkable not only for its unusual size, but also for a high level of participation in both longitudinal studies characterizing biomarker progression and pioneering prevention trials (see May 2012 news story and Crenezumab).

Currently, there are about 5,000 living members of the Colombian kindred spread among 25 families who live in a historically isolated region in the Andes Mountains. The pedigree spans five to seven generations, originating with a couple from the Basque region of Spain who settled in Colombia in the early 1700s. Nearly half of the living members of the kindred live in Medellín, the second largest city in Colombia, with the majority of the others scattered in outlying villages. Of the 5,000 living members, it is estimated that nearly 1,000 carry the mutation, with about 400 confirmed carriers.

In this kindred, mutation carriers typically develop memory deficits in the third decade of life, followed by progressive impairments in other cognitive domains, such as verbal fluency. Mild cognitive impairment sets in around age 45 and dementia by age 50. Although the vast majority develop dementia between age 45 and 50, a 30-year window has been documented, with rare cases experiencing onset as early as age 30 or as late as age 65. The mutation is, however, fully penetrant. The median duration from onset of dementia to death is approximately 10 years, ranging from nine to 12 years, with 59 being the median age at death (Acosta-Baena et al., 2011). There is no evidence of anticipation in subsequent generations.

The majority of E280A carriers present with symptoms fairly typical of AD, including progressive memory loss and changes in personality and behavior; however, there is phenotypic variability. For example, some patients also present with epilepsy, verbal impairment, and cerebellar ataxia. Specifically, mutation carriers present with memory impairment (100 percent), behavioral changes (94 percent), language impairment (e.g., aphasia, 81 percent), headache (73 percent), gait difficulties (65 percent), seizures and myoclonus (45 percent), and cerebellar signs and Parkinsonism (each 19 percent) (reviewed in Sepulveda-Falla et al., 2012). Severe headaches appear to be a frequent prodromal symptom, typically occurring several years before dementia onset (Lopera et al., 1997).

Related carriers have been identified in other Colombian regions (Arango et al., 2001) and in other countries (Kwok et al., 1997). In addition, the same E280A mutation was identified in a Japanese family with two affected family members and a mean age of onset of 57 years (Tanahashi et al., 1996).

Neuropathology

Those affected by the E280A mutation show neuropathology consistent with a diagnosis of AD, including severe brain atrophy, Aβ pathology, and hyperphosphorylated tau-related pathology. Aβ42 may be particularly abundant in the cerebral cortex, hippocampus, cerebellum, midbrain, and basal ganglia. Prominent cerebral amyloid angiopathy has also been seen. Of note, cerebellar damage appears to be a common feature, including ubiquitin–positive plaques in the molecular layer surrounded by reactive astrocytes and dystrophic neurites (Lemere et al., 1996).

A subset of patients suffering from seizures reported greater neuronal loss and hippocampal sclerosis than patients without epileptic seizures (Velez-Pardo et al., 2004).

Many studies are looking for pathological changes in presymptomatic E280A carriers using neuroimaging and CSF analysis (see Mar 2011 news story). One of the earliest differences between carriers and non-carriers may be hyperactivation of the right anterior hippocampus during the encoding of novel associations, suggesting that carriers push their hippocampal circuitry harder to achieve equivalent performance (Quiroz et al., 2010).

Biological Effect

In vitro, this mutation increases the Aβ42/Aβ total ratio in COS-1 cells co-transfected with APP695 (Murayama et al., 1999). A similar shift toward Aβ42 has also been observed in other cell types, including Neuro2A mouse neuroblastoma cells and C6 rat glioblastoma cells. The E280A mutation does not appear to affect the endoproteolysis of the presenilin-1 protein (Kaneko et al., 2007). Although other presenilin-1 mutations have been associated with elevated cell cycle arrest, the E280A mutation appears to have a relatively small effect (Janicki et al., 2000).

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References

News Citations

  1. NIH Director Announces $100M Prevention Trial of Genentech Antibody
  2. Detecting Familial AD Ever Earlier: Subtle Memory Signs 15 Years Before

Therapeutics Citations

  1. Crenezumab

Paper Citations

  1. . Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 2011 Mar;10(3):213-20. PubMed.
  2. . Phenotypic Profile of Early-Onset Familial Alzheimer's Disease Caused by Presenilin-1 E280A Mutation. J Alzheimers Dis. 2012 Jan 1;32(1):1-12. PubMed.
  3. . Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997 Mar 12;277(10):793-9. PubMed.
  4. . Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet. 2001 Oct 1;103(2):138-43. PubMed.
  5. . Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.
  6. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  7. . The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med. 1996 Oct;2(10):1146-50. PubMed.
  8. . CA1 hippocampal neuronal loss in familial Alzheimer's disease presenilin-1 E280A mutation is related to epilepsy. Epilepsia. 2004 Jul;45(7):751-6. PubMed.
  9. . Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease. Ann Neurol. 2010 Dec;68(6):865-75. PubMed.
  10. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  11. . Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 deltaT440 mutant associated with familial Lewy body disease and variant Alzheimer's disease. J Neurosci. 2007 Nov 28;27(48):13092-7. PubMed.
  12. . Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. Neurobiol Aging. 2000 Nov-Dec;21(6):829-36. PubMed.

Further Reading

Papers

  1. . Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol. 2003 Aug;54(2):163-9. PubMed.
  2. . Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. J Clin Invest. 2014 Apr 1;124(4):1552-67. Epub 2014 Feb 24 PubMed.
  3. . Spectral Analysis of EEG in Familial Alzheimer's Disease with E280A Presenilin-1 Mutation Gene. Int J Alzheimers Dis. 2014;2014:180741. Epub 2014 Jan 2 PubMed.
  4. . The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers. J Clin Psychiatry. 2014 Jun;75(6):652-60. PubMed.
  5. . Association between HFE 187 C>G (H63D) mutation and early-onset familial Alzheimer's disease PSEN-1 839A>C (E280A) mutation. Ann Hematol. 2008 Aug;87(8):671-3. PubMed.
  6. . E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Hum Mutat. 1997;10(3):186-95. PubMed.
  7. . Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014 Jul 15;83(3):253-60. Epub 2014 Jun 13 PubMed.
  8. . Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database Clinical trial of Crenezumab in Preclinical E280A Mutation Carriers

Primary Papers

  1. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  2. . Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997 Mar 12;277(10):793-9. PubMed.

Other mutations at this position

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