Mutations

PSEN1 I202F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659407 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATC to TTC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a Welsh kindred affected by familial Alzheimer’s disease (Church et al., 2011). The average age of onset in this family was 53 years (range: 49 to 59 years). The proband developed progressive forgetfulness at the age of 49. By 53, she was disoriented, with a jerky, myoclonic postural tremor as well as a tremor at rest. The reported pedigree shows seven affected family members over two generations. One of the proband’s six siblings developed memory impairment at the age of 53 and died at the age of 59. The proband’s father was one of nine siblings, of whom four developed dementia. Overall, the clinical phenotype in this family consisted of an amnestic syndrome with some members also exhibiting language deficits, visuo-spatial difficulties, and/or myoclonus.

This mutation appears to segregate with disease in this family: it was confirmed present in three affected family members.

A subsequent report described a woman from the same kindred whose episodic memory started gradually declining at age 48 (Ryan et al., 2015). At age 53, she had significant impairment of immediate and delayed recall memory, as well as finger myoclonus. Her condition steadily declined, with a sub-acute period of cognitive and behavioral deterioration at age 57. She was homozygous for the APOE 4 allele. Similar symptoms were experienced by her father, at age 67, and two of her sisters in their early 50s.

Neuropathology

In the case reported by Ryan et al., neuropathology was consistent with end-stage AD with severe cerebral amyloid angiopathy (Ryan et al., 2015). The amyloid angiopathy included chronic inflammatory infiltrate surrounding some of the cortical and leptomeningeal blood vessels. Lewy pathology was reported predominantly in the amygdala. Two years prior, an MRI scan revealed white matter hyperintensities, particularly in a parieto-occipital distribution, associated with marked focal loss of sulcal spaces, suggesting edema. These alterations were similar to those known as ARIA (amyloid-related imaging abnormalities) observed in some patients participating in amyloid-modifying therapy trials. A follow-up MRI nine months later revealed some degree of spontaneous improvement in the severity of white matter change and edema.

Biological Effect

In vitro assays using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased production of Aβ42 and Aβ40 (Bai et al., 2015; Sun et al., 2017). The Aβ42/Aβ40 ratio was reported as approximately three-fold greater than that generated by wild-type PSEN1 in one study (Bai et al., 2015), but similar to wild-type in another (Sun et al., 2017). In assays using membrane samples isolated from the brain of a mutation carrier, the Aβ42/Aβ40 ratio was found to be elevated, although changes in de novo production of Aβ40 and Aβ42 compared with samples from healthy brains failed to reach significance (Szaruga et al., 2015). Aβ38 production, however, was reduced relative to controls, as was the Aβ38/Aβ42 ratio. These findings suggest impairment of the fourth catalytic cleavage in the carboxypeptidase-like digestion of Aβ into shorter peptides.

Last Updated: 23 Jun 2019

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References

Paper Citations

  1. . A novel presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer's disease. Neurobiol Aging. 2011 Mar;32(3):556.e1-2. Epub 2010 Dec 7 PubMed.
  2. . Spontaneous ARIA (amyloid-related imaging abnormalities) and cerebral amyloid angiopathy related inflammation in presenilin 1-associated familial Alzheimer's disease. J Alzheimers Dis. 2015;44(4):1069-74. PubMed.
  3. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
  4. . 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.
  5. . 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.

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.

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer's disease. Neurobiol Aging. 2011 Mar;32(3):556.e1-2. Epub 2010 Dec 7 PubMed.

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