Category: Parkinson's Disease: Genetics
Objective: To identify novel genes involved in the familial form of Parkinson’s disease (PD) in the Indian population.
Background: Most of the familial forms of genes implicated in PD have been identified in the European population with limited transferability in ethnically diverse populations as the Indian population.
Method: Exome sequencing in a large PD family from India with multiple affected (4 affected and 2 unaffected) was performed. The targeted resequencing was performed in an independent cohort of 714 PD cases and 362 controls from the Indian population. Furthermore, whole-exome sequencing (WES) data from the IPDGC, which includes 1,167 PD cases and 1,685 controls (post-QC) and additional 500 exomes (250 PD cases and 250 controls) from the Helmholtz database were screened to assess and identify the frequency of the novel variants in the European population. RNA-sequencing from striatum, cortex, and cerebellum from alpha-synuclein (α-SNCA) knock out (KO) mouse model was performed to assess whether α-SNCA modifies the expression of a novel gene.
Results: We found a missense mutation, c.2698G>A (p.Glu900Lys), in the GRIN2D gene, encoding Glutamate Ionotropic Receptor N-methyl-D-aspartate (NMDA) Type Subunit 2D, in all four affected family members. Targeted resequencing identified additional six nonsynonymous missense variants, including familial mutation, p.Glu900Lys, in sporadic PD cases in the Indian population. Computational modelling maps the novel variants at the tetramer interface on the intracellular side of the channel, possibly impacting the protein function. WES data from the IPDGC and Helmholtz database revealed additional two nonsynonymous missense variants present only in PD cases in the European population. We observed a non-significant trend towards the lower expression of the GRIN2D in the cortex in the young vs. old α-SNCA KO mouse model.
Conclusion:
Our findings implicate the role of the rare mutations in the GRIN2D gene in the pathogenesis of PD and emphasize the impact of NMDA receptor perturbations on PD pathogenesis.
To cite this abstract in AMA style:
A. Kishore, M. Sturm, J. Shin, S. Grover, F. Raimondi, C. Blauwendraat, S. Robert, G. Sarma, N. Casadei, P. Lichtner, A. Kumar-Sreelatha, J. Winkelmann, R. Krüger, A. Singleton, T. Gasser, P. Seth, J. Roeper, O. Riess, M. Sharma. GRIN2D is a cause of autosomal dominant form of Parkinson’s disease [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/grin2d-is-a-cause-of-autosomal-dominant-form-of-parkinsons-disease/. Accessed June 14, 2025.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/grin2d-is-a-cause-of-autosomal-dominant-form-of-parkinsons-disease/