Objective: In this study we investigated the association of GRN damaging mutations in the etiology of Lewy body dementia.

Background: Lewy body dementia (LBD) is the second most common form of neurodegenerative dementia, accounting for 1.4 million cases in the United States. The disorder is characterized by neuropsychiatric, cognitive, motor, and autonomic symptoms. The causes of LBD are poorly understood, and no cure is available for this progressive and fatal disease.
Progranulin, encoded by GRN, is a growth factor that plays an important role in several cellular functions, including regulation of lysosomal homeostasis and microglia activation. GRN damaging mutations are associated to frontotemporal degeneration (FTD) with TDP-43-positive inclusions. However, GRN variants have been recently described as risk factors in patients with Alzheimer’s disease and Parkinson’s disease, expanding the spectrum of the gene in neurodegeneration.

Method: We analyzed whole-genome sequencing data from 2,591 LBD patients and 4,032 neurologically healthy controls of European-ancestry to investigate the association of GRN loss-of-function (LOF) mutations in the etiology of LBD. The patients were diagnosed with pathologically definite (69%) or clinically probable (31%) LBD. All control subjects had no family history of dementia or neurological deficits on neurological examination.

Results: We identified six heterozygous GRN LOF mutations in six LBD cases and a control subject. Particularly, we detected a stop mutation (p.R493X) in two patients, four patients carrying a frameshift mutation (p.Q130Sfs*124, p.T382Sfs*29, p.E498Dfs*11) or a missense mutation (p.A9V), and a stop mutation (p.R535X) in a control. All variants were predicted to be pathogenic or likely pathogenic, and the gene burden test revealed a significant enrichment of LOF mutations in LBD cases compared to controls (SKAT-O; p-value = 0.0162). Two cases reported a strong family history of dementia. Histopathological examination detected widespread Lewy body disease and type A TDP-43-positive inclusions in three patients, emphasizing the molecular overlap between LBD and FTD.

Conclusion: Our study expands the pathogenic role of GRN in neurodegeneration, implicating LOF mutations of the gene in the etiology of LBD. Although rare, the molecular screening of GRN should be considered to define a molecular diagnosis of LBD, particularly in patients with a positive family history of dementia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/deleterious-grn-mutations-a-new-player-in-the-etiology-of-lewy-body-dementia/