Overview

Pathogenicity: Atypical Dementia : Not Classified
Clinical Phenotype: Atypical Dementia
Position: (GRCh38/hg38):Chr1:226885546 C>G
Position: (GRCh37/hg19):Chr1:227073247 C>G
dbSNP ID: rs28936380
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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

PSEN2 with the T122R variant was transfected into human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing tagged APP-695 (Liu et al., 2024). Although computer modeling predicted the variant has only minor effects on Aβ42 and Aβ40 production (Soto-Ospina et al., 2021), the Aβ42/Aβ40 ratio was increased (0.25 vs 0.15) and the Aβ37/Aβ42 ratio decreased (0.23 vs 0.44) in the cells’ conditioned media compared to cells transfected with wildtype PSEN2, as reported in a preprint (Liu et al., 2024). Both ratios are indicators of AD pathogenicity, with the Aβ37/Aβ42 ratio reported to outperform the Aβ42/Aβ40 ratio for PSEN1 variants (Liu et al., 2022, Apr 2022 news).

T122R was also one of several PSEN2 variants 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). Computer modeling of PSEN2 structure and function predicted the variant may alter the phosphorylation status of position 122, as well as of T125 which could affect calcium dynamics (Soto-Ospina et al., 2021).

Also of note, T122R’s homolog in PSEN1, T116R fulfilled several pathogenic ACMG-AMP criteria and, like PSEN2 T122R, increased the Aβ42/Aβ40 ratio (T116R:0.51 vs WT:0.15) and decreased the Aβ37/Aβ42 ratio (T116R:0.10 vs WT:0.41) (Liu et al., 2024 preprint). Across multiple PSEN1 and PSEN2 variants, the effects of PSEN1/PSEN2 homologs  were correlated.

PSEN2 T122R's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

Although this variant fulfilled several ACMG-AMP criteria (Richards et al., 2015), it was not classified by Alzforum, because carriers were not diagnosed with a Mendelian disorder.

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References

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022

Mutations Citations

1. PSEN1 T116R

Paper Citations

1. Binetti G, Signorini S, Squitti R, Alberici A, Benussi L, Cassetta E, Frisoni GB, Barbiero L, Feudatari E, Nicosia F, Testa C, Zanetti O, Gennarelli M, Perani D, Anchisi D, Ghidoni R, Rossini PM. Atypical dementia associated with a novel presenilin-2 mutation. Ann Neurol. 2003 Dec;54(6):832-6. PubMed.
2. Soto-Ospina A, Araque Marín P, Bedoya GJ, Villegas Lanau A. Structural Predictive Model of Presenilin-2 Protein and Analysis of Structural Effects of Familial Alzheimer's Disease Mutations. Biochem Res Int. 2021;2021:9542038. Epub 2021 Nov 29 PubMed.
3. Liu L, Schultz S, Saba A, Yang H-S, Li A, Selkoe D, Chhatwal J. The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1. 2024 Jun 28 10.1101/2024.06.22.600217 (version 1) bioRxiv.
4. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
5. Zatti G, Burgo A, Giacomello M, Barbiero L, Ghidoni R, Sinigaglia G, Florean C, Bagnoli S, Binetti G, Sorbi S, Pizzo P, Fasolato C. 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.
6. Giacomello M, Barbiero L, Zatti G, Squitti R, Binetti G, Pozzan T, Fasolato C, Ghidoni R, Pizzo P. 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.
7. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Other Citations

1. Liu et al., 2024

Further Reading

No Available Further Reading