Pathogenicity: Atypical Dementia : Pathogenic
Clinical Phenotype: Atypical Dementia
Reference Assembly: GRCh37/hg19
Position: Chr1:227073247 C>G
dbSNP ID: rs28936380
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACG to AGG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6


This mutation was first described in a three-generation Italian kindred with hereditary dementia. The proband experienced disease onset at age 55, with increasing attentional difficulties, language impairment, and apraxia. After five years he was bedridden and unable to speak. The proband was one of four siblings. His two monozygotic twin sisters both carried the mutation, but only one had symptomatic disease at age 60 (disease onset at age 57). The mutation was absent in the fourth, unaffected sibling. Other clinical features observed in this kindred included behavioral disturbances, including disinhibition and eating disorders, language deficits, and attention impairment, reminiscent of frontotemporal dementia (Binetti et al., 2003).


MRI showed variable cortical and subcortical atrophy in the proband and his affected sibling (Binetti et al., 2003).

Biological Effect

This mutation was one of several in PSEN2 shown to lower calcium ion release from intracellular stores (Zatti et al., 2006). Fibroblasts cultured from carriers of the PSEN2 T122R mutation also had reduced intracellular calcium compared with control fibroblasts cultured from either an unaffected sibling or unrelated individuals (Giacomello et al., 2005).


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Paper Citations

  1. . Atypical dementia associated with a novel presenilin-2 mutation. Ann Neurol. 2003 Dec;54(6):832-6. PubMed.
  2. . Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels. Cell Calcium. 2006 Jun;39(6):539-50. PubMed.
  3. . Reduction of Ca2+ stores and capacitative Ca2+ entry is associated with the familial Alzheimer's disease presenilin-2 T122R mutation and anticipates the onset of dementia. Neurobiol Dis. 2005 Apr;18(3):638-48. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Atypical dementia associated with a novel presenilin-2 mutation. Ann Neurol. 2003 Dec;54(6):832-6. PubMed.

Other mutations at this position


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