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KMID : 1034820190150030345
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Molecular & Cellular Toxicology
2019 Volume.15 No. 3 p.345 ~ p.352
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Novel GRN mutations in Koreans with Alzheimer’s disease
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Shen Lingyan
An Seong-Soo A.
Bagyinszky Eva
Giau Vo Van
Choi Seong-Hye
Kim Sang-Yun
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Abstract
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Backgrounds Alzheimer’s disease (AD) and fronto-temporal dementia (FTD) are the two most common neurodegenerative diseases leading to early onset dementia (<65 years). Mutations in the amyloid precursor protein, presenilin, and presenilin 2 genes are involved in some cases of familial early-onset AD (EOAD), while the microtubule-associated protein tau (MAPT) and pro-granulin (GRN) mutations have been mainly identifed in FTD patients. Clinically, FTD was often misdiag-nosed and confused with AD or psychiatric disorders, which could be a challenge in disease diagnosis.
Methods: We performed mutation analysis of GRN in 89 Korean patients with clinically diagnosed EOAD. In silico predictions were also performed for the variants to estimate their role in different disorders.
Results: No pathological mutations in MAPT was identified, but we identified two novel genetic variations in the GRN gene: p.Leu585Phe (c.1767G>T) and c.IVS8+23_+26delTGGG, which occurred independently in two EOAD patients (frequenct of 2/89, 2.2%). Using a combination of clinical and association studies, in silico prediction, and 3-D modeling software, we suggest that both mutations are probably pathogenic and involved in FTD.
Conclusion: Our data suggest that it would be important to re-examine EOAD patients who had been diagnosed when the FTD spectrum was not well described and the causative FTD genes had not yet been identifed. In addition, we propose initially analyzing genes associated with the frst form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.
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KEYWORD
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GRN, EOAD, AD, Mutation, Korean
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