Mutations

PSEN1 E120G

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640294 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to GGA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation is associated with early onset Alzheimer's disease in a Spanish kindred (Lladó et al., 2010Gómez-Tortosa et al., 2010). This family was noted to have a particularly homogeneous age at onset (around 39 to 40 years), epileptic activity, and very rapid cognitive and functional deterioration.

The proband began to experience memory loss and progressive cognitive decline in his 30s. As the disease progressed, he developed seizures and difficulties with gait. He died at the age of 44. His father, paternal uncle, and sister were also affected. The father had developed behavioral disturbances and memory deficits around age 39 and died at age 42. He had generalized seizures. His homozygous twin brother also developed symptoms in his late 30s and died at age 42. The proband’s sister began having recurrent generalized seizures at age 39. Memory deficits began simultaneously and progressed to substantial cognitive deterioration within two years. The mutation was shown to segregate with disease in this family (Gómez-Tortosa et al., 2010).

Neuropathology

Neuropathological examination of the proband’s brain revealed frequent amyloid plaques and neurofibrillary tangles along with severe amyloid angiopathy (Lladó et al., 2010).

Biological Effect

In membrane samples from a patient brain incubated with tagged APP-C99 substrate, production rates of Aβ38 and Aβ40 were decreased compared with control samples (Szaruga et al., 2015). The mutation appears to impair the fourth γ-secretase cleavage in the Aβ production line(s) that sequentially digest Aβ into shorter peptides, as revealed by a decrease in the Aβ38/Aβ42 (product/substrate) ratio. Moreover, in mouse embryonic fibroblasts transfected with PSEN1 E120G, APP intracellular domain production was approximately 30 percent of wild-type levels and the Aβ38/Aβ42 ratio was approximately 10-fold reduced, suggesting impairment of the fourth γ-secretase cleavage in the Ab production lines that sequentially digest Aβ49 and Aβ48 into shorter peptides. Consistent with these findings, another cell-based study reported an increased Aβ42/Aβ40 ratio (Sarroca et al., 2016).

In silico, PolyPhen predicted this mutation is probably damaging (Gómez-Tortosa et al., 2010).

Last Updated: 18 May 2019

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . [New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer's disease]. Neurologia. 2010 Jan-Feb;25(1):13-6. PubMed.
  2. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
  3. . Qualitative changes in human γ-secretase underlie familial Alzheimer's disease. J Exp Med. 2015 Nov 16;212(12):2003-13. Epub 2015 Oct 19 PubMed.
  4. . Preservation of cell-survival mechanisms by the presenilin-1 K239N mutation may cause its milder clinical phenotype. Neurobiol Aging. 2016 Oct;46:169-79. Epub 2016 Jul 15 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . [New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer's disease]. Neurologia. 2010 Jan-Feb;25(1):13-6. PubMed.
  2. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. 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.