Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659570 A>C
dbSNP ID: rs63751320
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAT to TCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was found in a young man with rapid-progressing dementia emerging at 25 years of age, (Miklossy et al., 2003). His initial symptoms included delusional thinking, obsessive-compulsiveness, and aggressiveness. Memory loss with changes in judgement capacity, dysarthria, apathy, agraphia, and acalculia developed rapidly in the subsequent year. He also presented with corticospinal signs (tetraspasticity, bilateral Babinski), athetosis, myoclonus, static and kinetic cerebellar ataxia astereognosia, and deficits in proprioception and graphesthesia. The man died three years after disease onset. The proband’s mother also died at an early age, 32, after disease onset at age 30. She suffered from disorientation, verbal perseverations, laconic speech, stereotypic behavior, apraxia, catatonic postures, dysarthria, visual field deficits, static and kinetic cerebellar ataxia, and corticospinal and mild extrapyramidal signs. The mutation was absent from 100 unrelated individuals.

Neuropathology was consistent with AD, but particularly widespread and severe (Suvà et al., 1999; Miklossy et al., 2003). In the proband, diffuse, predominantly cortical atrophy was observed (Braak grade VI). Abundant plaque and tangle formation was found in the entorhinal cortex, hippocampus, as well as in the frontal and parietal associative cortices. Pathology in the primary motor cortex correlated well with the pyramidal changes, including tetraspasticity. Numerous plaques and tangles were also found in the basal ganglia, thalamus, and the substantia nigra. Moreover, neurofibrillary tangles were reported in the locus coeruleus, raphe nuclei, and the pontine reticular formation, and plaques were found in the mesencephalon, pons, medulla oblongata, cervical level of the spinal cord, and cerebellum. Plaque types included cotton-wool, amorphous, and mature. Clinical reports from the proband’s mother indicate she also had neuropathology consistent with AD.

Biological Effect
Elevated levels of both Aβ40 and Aβ42 were detected in frontal cortex by immunoblot and ELISA (Miklossy et al., 2003). In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, an approximately 8-fold increase in the Aβ42/Aβ40 ratio was reported, although production of both peptides was reduced compared with wild-type PSEN1 (Sun et al., 2017).

Last Updated: 11 Apr 2019


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Paper Citations

  1. . Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease. Neurobiol Aging. 2003 Sep;24(5):655-62. PubMed.
  2. . Primary motor cortex involvement in Alzheimer disease. J Neuropathol Exp Neurol. 1999 Nov;58(11):1125-34. 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease. Neurobiol Aging. 2003 Sep;24(5):655-62. PubMed.

Other mutations at this position


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