Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73659512 T>A
dbSNP ID: rs63750858
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTT to ATT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was found in a Japanese man with very early onset AD with spastic paraparesis, but no known family history of the disease (Sodeyama et al., 2001). His first neurological symptom was gait disturbance at age 31. A year later, he developed memory loss and cognitive impairment, both of which progressed rapidly, with dementia diagnosed at age 33. Also at 33, he presented with diffuse hyperreflexia, ataxia in all limbs, and bilateral Babinski’s sign. None of the proband’s known family members had developed similar symptoms, and none were tested for the mutation. The mutation was absent from 197 Japanese patients, including 73 non-demented controls without a CNS disorder and 59 patients with sporadic AD, as well as from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathological data are unavailable, but 2DG-PET and SPECT imaging of the proband’s brain showed metabolic and perfusion patterns typical of AD, with hypometabolism and hypoperfusion in the bilateral temporoparietal areas, including the primary sensory and motor cortices (Sodeyama et al., 2001). MRI revealed diffuse cerebral cortical atrophy.

Biological Effect
In an in vitro assay using APP C99 as a substrate, Aβ42 production was severely inhibited and Aβ40 was undetectable (Bai et al., 2015). A subsequent in vitro study also found decreased production of both Aβ40 and Aβ42, but the Aβ42/Aβ40 ratio was similar to that generated by wild-type PSEN1 (Sun et al., 2017). Codon 237 is evolutionarily conserved in human PSEN1, human PSEN2, mouse PSEN1, and Caenorhabditis elegans Sel-12 protein (Sodeyama et al., 2001). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, the phenylalanine at this position helps form a hydrophobic pocket in the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Last Updated: 10 Sep 2021


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Very early onset Alzheimer's disease with spastic paraparesis associated with a novel presenilin 1 mutation (Phe237Ile). J Neurol Neurosurg Psychiatry. 2001 Oct;71(4):556-7. PubMed.
  2. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
  3. . 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.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  5. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Very early onset Alzheimer's disease with spastic paraparesis associated with a novel presenilin 1 mutation (Phe237Ile). J Neurol Neurosurg Psychiatry. 2001 Oct;71(4):556-7. PubMed.

Other mutations at this position


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