Mutations

PSEN2 T122R

Overview

Pathogenicity: Atypical Dementia : Not Classified
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

Findings

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. Although only one of the twins had symptomatic disease at age 60 (disease onset at age 57), the other one's levels of Aβ42 in cerebrospinal fluid were comparable to those of sporadic AD patients, and her tau levels were increased compared with controls. The mutation was absent in the fourth, unaffected sibling who was 57 years old, the same age as the family's mean age at onset. Thus, cosegregation with disease was not firmly established. 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).

This mutation was absent from the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology

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). Moreover, this variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

Last Updated: 02 Nov 2021

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References

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

No Available Further Reading

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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