Mutations

PSEN1 L226F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73659479 C>T
dbSNP ID: rs63750487
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTC to TTC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This presenilin-1 mutation has been reported in at least three individuals from disparate countries. It is associated with an early and aggressive disease phenotype.

The L226F mutation was first detected in a Polish man who had been diagnosed with frontotemporal dementia at the age of 33; however, postmortem examination later revealed Alzheimer’s disease. Clinically, he met Lund and Manchester consensus criteria (1994) for FTD. His disease presented with prominent behavioral symptoms, including inertia, social disinhibition, and repetitive and stereotyped behavior. He later developed severe deterioration of short-term memory. He died mute at the age of 38. His mother had also developed cognitive deterioration at the age of 33 and died at 44 with unspecified dementia. Segregation of the mutation with disease could not be assessed due to lack of DNA from family members (Zekanowski et al., 2006).

This mutation was also identified in a Spanish woman. She developed symptoms at the age of 33, including dysarthria, nonfluent speech, depression, and frontal signs. By the age of 36 she had developed mild parkinsonism, including bilateral tremor, limb bradykinesia, and reflex myoclonus. She died at the age of 42. Her father had also died at 42 following a six-year course of cognitive deterioration. Segregation of the mutation with disease could not be assessed due to lack of DNA samples (Gómez-Tortosa et al., 2010).

The L226F mutation was recently identified in a Korean woman with early onset AD (Bagyinszky et al., 2016). Her symptoms started at age 37 with anxiety and paranoia and then progressed into severe cognitive and memory deficits which affected activities of daily living. Her speech deteriorated, becoming nonfluent and then mute. Her movements slowed and she developed muscle rigidity. She was bedridden for 18 months before her death at age 44. This mutation may have arisen de novo. Her family members were not carriers and there were no other known cases of dementia in her small family tree.

Neuropathology

Despite a clinical diagnosis of FTD at the time of his death, postmortem examination of the Polish man with this mutation revealed definite AD according to CERAD and NIA-Reagan criteria (Zekanowski et al., 2006).

Neuropathology was not assessed in the Spanish woman with this mutation; however, CT showed diffuse cortical atrophy, especially in the parietal lobes (Gómez-Tortosa et al., 2010). Likewise, neuropathological assessment was not available for the Korean woman; however, MRI showed bilateral atrophy in the hippocampus as well as in the parietal cortex. PET imaging showed severe hypometabolism in the parietal cortex (Bagyinszky et al., 2016).

Biological Effect

When expressed in HEK293 cells co-expressing APP with the Swedish mutation, mutant presenilin-1 resulted in increased Aβ42, Aβ40, and Aβ42/Aβ40, compared with cells expressing wild-type presenilin-1 (Bialopiotrowicz et al., 2012). Similar results were obtained in vitro using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate (Sun et al., 2017). In silico this mutation was predicted to be "probably damaging" by PolyPhen2 (Bagyinszky et al., 2016).

Last Updated: 23 May 2019

Comments

  1. This study and others imply that some of the PS mutations may induce pathological gain-of-function phenotypes.

    View all comments by Takaomi Saido

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References

Paper Citations

  1. Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry. 1994 Apr;57(4):416-8. PubMed.
  2. . Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol. 2006 Jul;200(1):82-8. PubMed.
  3. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
  4. . PSEN1 L226F mutation in a patient with early-onset Alzheimer's disease in Korea. Clin Interv Aging. 2016;11:1433-1440. Epub 2016 Oct 12 PubMed.
  5. . Highly Pathogenic Alzheimer's Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes. J Alzheimers Dis. 2012 Jan 1;32(2):397-415. PubMed.
  6. . 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.

Other Citations

  1. Swedish mutation

Further Reading

Papers

  1. . 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.
  2. . A genetic screen of the mutations in the Korean patients with early-onset Alzheimer's disease. Clin Interv Aging. 2016;11:1817-1822. Epub 2016 Dec 15 PubMed.

Protein Diagram

Primary Papers

  1. . Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol. 2006 Jul;200(1):82-8. PubMed.

Other mutations at this position

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