Mutations

PSEN1 F176L

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Genome Build: 105
Position: Chr14:73653606 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Genomic Region: Exon 6
Mutation Type: Point, Missense
Codon Change: TTT to CTT

Findings

This mutation was reported in the DNA of Auguste Deter, Alois Alzheimer's famous patient. The discovery of this novel presenilin-1 mutation offered an explanation to the longstanding question regarding the genetic basis of Deter's disease; however, the strength of this finding has since been called into question by a conflicting report.

Auguste D., as she is known to neuroscientists, was a German woman examined by Alzheimer in 1901 for symptoms of "presenile dementia." Her condition, characterized by memory loss and severe behavioral changes, including extreme jealousy, aggression, hallucinations, and delusions, led to her institutionalization in Frankfurt at the age of 51. She declined rapidly and died in 1906. Alzheimer examined her brain, and he reported his clinical and neuropathological findings in the landmark paper "A Characteristic Disease of the Cerebral Cortex" (Alzheimer, 1907).

In the 1990s, slides of Deter's sectioned cortex were rediscovered in the basement of the Institute of Neuropathology at the University of Munich (Graeber, 1999). Examination of the cortex confirmed the original diagnosis (Graeber et al., 1998; Enserink et al., 1998). DNA extracted from the century-old specimen showed that Deter had been homozygous for APOE ε3 (Graeber et al., 1998). Partial sequencing of PSEN1 and PSEN2, specifically exons 5 and 6 of PSEN1 and exon 5 of PSEN2, revealed a novel T>C change in PSEN1 at codon 176 (Müller et al., 2013). However, a later study was not able to validate the presence of this variant in Deter's DNA (Rupp et al., 2014). The later study also analyzed PSEN1 (exons 4-12), APP (exons 16-17), and PSEN2 (exons 4-12), but found no non-synonymous variants that could account for her disease, concluding that an as-yet-unknown mutation may be to blame.

Neuropathology

According to a translation of Alzheimer's 1907 paper, Deter's autopsy showed "an evenly affected atrophic brain without macroscopic foci." Alzheimer also noted neurofibrillary tangles and neuronal loss, observing that, "Eventually the nucleus and cytoplasm disappeared, and only a tangled bundle of fibrils indicated the site where once the neuron had been located." He also observed amyloid plaques that he called "miliary foci" or the "deposition of a peculiar substance in the cerebral cortex." Modern-day neuropathological analysis has confirmed the diagnosis, finding abundant amyloid plaques and neurofibrillary tangles in the cortex (Graeber et al., 1998; Enserink et al., 1998). Interestingly, Alzheimer's original preparations did not include the hippocampus or entorhinal cortex.

Biological Effect

Unknown.

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References

Paper Citations

  1. . Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-gerichtliche Medizin. 1907 Jan;64:146-8.
  2. . No man alone: the rediscovery of Alois Alzheimer's original cases. Brain Pathol. 1999 Apr;9(2):237-40. PubMed.
  3. . Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D. Neurogenetics. 1998 Mar;1(3):223-8. PubMed.
  4. . First Alzheimer's diagnosis confirmed. Science. 1998 Mar 27;279(5359):2037. PubMed.
  5. . A presenilin 1 mutation in the first case of Alzheimer's disease. Lancet Neurol. 2013 Feb;12(2):129-30. PubMed.
  6. . A presenilin 1 mutation in the first case of Alzheimer's disease: revisited. Alzheimers Dement. 2014 Nov;10(6):869-72. Epub 2014 Aug 15 PubMed.

Further Reading

Primary Papers

  1. . A presenilin 1 mutation in the first case of Alzheimer's disease. Lancet Neurol. 2013 Feb;12(2):129-30. PubMed.

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