Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease
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 stu...
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BMC
2025-01-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-024-01661-y |
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| author | Elisa Rubino Maria Italia Elisa Giorgio Silvia Boschi Paola Dimartino Tommaso Pippucci Fausto Roveta Clara Maria Cambria Gabriella Elia Andrea Marcinnò Salvatore Gallone Ekaterina Rogaeva Flavia Antonucci Alfredo Brusco Fabrizio Gardoni Innocenzo Rainero |
| author_facet | Elisa Rubino Maria Italia Elisa Giorgio Silvia Boschi Paola Dimartino Tommaso Pippucci Fausto Roveta Clara Maria Cambria Gabriella Elia Andrea Marcinnò Salvatore Gallone Ekaterina Rogaeva Flavia Antonucci Alfredo Brusco Fabrizio Gardoni Innocenzo Rainero |
| author_sort | Elisa Rubino |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a3279aab87a4466fa3419f7eb0f11d5e |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-a3279aab87a4466fa3419f7eb0f11d5e2025-01-19T12:12:58ZengBMCAlzheimer’s Research & Therapy1758-91932025-01-0117111110.1186/s13195-024-01661-yExome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's diseaseElisa Rubino0Maria Italia1Elisa Giorgio2Silvia Boschi3Paola Dimartino4Tommaso Pippucci5Fausto Roveta6Clara Maria Cambria7Gabriella Elia8Andrea Marcinnò9Salvatore Gallone10Ekaterina Rogaeva11Flavia Antonucci12Alfredo Brusco13Fabrizio Gardoni14Innocenzo Rainero15Department of Neuroscience “Rita Levi Montalcini”, University of TurinDepartment of Pharmacological and Biomolecular Sciences, University of MilanDepartment of Molecular Medicine, University of PaviaDepartment of Neuroscience “Rita Levi Montalcini”, University of TurinDepartment of Molecular Medicine, University of PaviaMedical Genetics Unit, IRCCS Azienda Ospedaliero-UniversitariaDepartment of Neuroscience “Rita Levi Montalcini”, University of TurinDepartment of Medical Biotechnology and Translational Medicine (BIOMETRA), University of MilanDepartment of Neuroscience “Rita Levi Montalcini”, University of TurinDepartment of Neuroscience “Rita Levi Montalcini”, University of TurinCenter for Alzheimer’s Disease and Related Dementias, Department of Neuroscience and Mental Health, AOU Città della Salute e della Scienza di Torino, University HospitalTanz Centre for Research in Neurodegenerative Diseases, University of TorontoDepartment of Medical Biotechnology and Translational Medicine (BIOMETRA), University of MilanDepartment of Neuroscience “Rita Levi Montalcini”, University of TurinDepartment of Pharmacological and Biomolecular Sciences, University of MilanDepartment of Neuroscience “Rita Levi Montalcini”, University of TurinAbstract 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.https://doi.org/10.1186/s13195-024-01661-yAlzheimer’s diseaseNMDARGRIN2CGluN2C14-3-3 |
| spellingShingle | Elisa Rubino Maria Italia Elisa Giorgio Silvia Boschi Paola Dimartino Tommaso Pippucci Fausto Roveta Clara Maria Cambria Gabriella Elia Andrea Marcinnò Salvatore Gallone Ekaterina Rogaeva Flavia Antonucci Alfredo Brusco Fabrizio Gardoni Innocenzo Rainero Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease Alzheimer’s Research & Therapy Alzheimer’s disease NMDAR GRIN2C GluN2C 14-3-3 |
| title | Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease |
| title_full | Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease |
| title_fullStr | Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease |
| title_full_unstemmed | Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease |
| title_short | Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease |
| title_sort | exome sequencing reveals a rare damaging variant in grin2c in familial late onset alzheimer s disease |
| topic | Alzheimer’s disease NMDAR GRIN2C GluN2C 14-3-3 |
| url | https://doi.org/10.1186/s13195-024-01661-y |
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