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Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease

Articolo
Data di Pubblicazione:
2025
Abstract:
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with both genetic and environmental factors contributing to its pathogenesis. While early-onset AD has well-established genetic determinants, the genetic basis for late-onset AD remains less clear. This study investigates a large Italian family with late-onset autosomal dominant AD, identifying a novel rare missense variant in GRIN2C gene associated with the disease, and evaluates the functional impact of this variant. Methods: Affected and unaffected members from a Northern Italian family were included. Genomic DNA from family members was extracted and initially screened for pathogenic mutations in APP, PSEN1, and PSEN2, and screened for 77 genes associated with neurodegenerative conditions using NeuroX array assay. Exome sequencing was performed on three affected individuals and two healthy relatives. Bioinformatics analyses were conducted. Functional analysis was performed using primary neuronal cultures, and the impact of the variant was assessed through immunocytochemistry and electrophysiology. Results: Pathogenic variants were not identified in APP, PSEN1, or PSEN2, nor in the 77 genes in NeuroX array assay. Exome Sequencing revealed the c.3215C > T p.(A1072V) variant in GRIN2C gene (NM 000835.6), encoding for the glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 2C (GluN2C). This variant segregated in 6 available AD patients in the family and was absent in 9 healthy relatives. Primary rat hippocampal neurons overexpressing GluN2CA1072V showed an increase in NMDAR-induced currents, suggesting altered glutamatergic transmission. Surface expression assays demonstrated an elevated surface/total ratio of the mutant GluN2C, correlating with the increased NMDAR current. Additionally, immunocytochemistry revealed in neurons expressing the mutant variant a reduced colocalization between the GluN2C subunit and 14-3-3 proteins, which are known to facilitate membrane trafficking of NMDARs. Discussion: We identified a rare missense variant in GRIN2C associated with late-onset autosomal dominant Alzheimer's disease. These findings highlight the role of GluN2C-containing NMDARs in glutamatergic signaling and their potential contribution to AD pathogenesis.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
14-3-3; Alzheimer’s disease; GRIN2C; GluN2C; NMDAR
Elenco autori:
Rubino, Elisa; Italia, Maria; Giorgio, Elisa; Boschi, Silvia; Dimartino, Paola; Pippucci, Tommaso; Roveta, Fausto; Cambria, Clara Maria; Elia, Gabriella; Marcinnò, Andrea; Gallone, Salvatore; Rogaeva, Ekaterina; Antonucci, Flavia; Brusco, Alfredo; Gardoni, Fabrizio; Rainero, Innocenzo
Autori di Ateneo:
BRUSCO Alfredo
RAINERO Innocenzo
ROVETA FAUSTO
RUBINO Elisa
Link alla scheda completa:
https://iris.unito.it/handle/2318/2050170
Link al Full Text:
https://iris.unito.it/retrieve/handle/2318/2050170/1507013/13195_2024_Article_1661.pdf
Pubblicato in:
ALZHEIMER'S RESEARCH & THERAPY
Journal
Progetto:
Unveiling the hidden side of NEUrodevelopmental DIsorder Genetics (NEUDIG): a multidisciplinary pathway to new molecular diagnoses by integrating genomic, transcriptomic, and functional analyses.
  • Dati Generali
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Dati Generali

URL

https://pmc.ncbi.nlm.nih.gov/articles/PMC11730494/pdf/13195_2024_Article_1661.pdf

Aree Di Ricerca

Settori (22)


LS2_14 - Genetic diseases - (2024)

LS5_11 - Neurological and neurodegenerative disorders - (2024)

CIBO, AGRICOLTURA e ALLEVAMENTI - Agricoltura e Produzioni Vegetali

CIBO, AGRICOLTURA e ALLEVAMENTI - Allevamento e Produzioni Animali

CIBO, AGRICOLTURA e ALLEVAMENTI - Farmacologia Veterinaria

CIBO, AGRICOLTURA e ALLEVAMENTI - Miglioramento e difesa delle colture

CIBO, AGRICOLTURA e ALLEVAMENTI - Patologia e malattie degli animali

CIBO, AGRICOLTURA e ALLEVAMENTI - Scienze cliniche veterinarie

CIBO, AGRICOLTURA e ALLEVAMENTI - Tecnologie alimentari e microbiologia degli alimenti

INFORMATICA, AUTOMAZIONE e INTELLIGENZA ARTIFICIALE - Genetica, Omica e Bioinformatica

MEDICINA, SALUTE e BENESSERE - Diagnostica e Imaging

MEDICINA, SALUTE e BENESSERE - Disturbi neuropsichiatrici

MEDICINA, SALUTE e BENESSERE - Epidemiologia

MEDICINA, SALUTE e BENESSERE - Fisiologia comportamentale

MEDICINA, SALUTE e BENESSERE - Malattie neurologiche e neurodegenerative

MEDICINA, SALUTE e BENESSERE - Management del malato e delle malattie

MEDICINA, SALUTE e BENESSERE - Oncologia e Tumori

MEDICINA, SALUTE e BENESSERE - Prevenzione e corretti stili di vita

MEDICINA, SALUTE e BENESSERE - Psicologia clinica

MEDICINA, SALUTE e BENESSERE - Ricerca Traslazionale e Clinica

SCIENZE DELLA VITA e FARMACOLOGIA - Interazioni tra molecole, cellule, organismi e ambiente

SCIENZE DELLA VITA e FARMACOLOGIA - Sviluppo del sistema nervoso e plasticità
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