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Novel GRN mutations in Koreans with Alzheimer’s disease

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Abstract

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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Acknowledgements

This research was supported by a National Research Foundation of Korea (NRF) Grants awarded by the Korean government (MEST, No. 2017R1A2B 4012636 & 2017R1C1B5017807). The authors would like to express their gratitude to the proband patient and his family members for their time and support.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Seongnam-si, Gyeonggi-do, Republic of Korea

    Lingyan Shen, Seong Soo A. An, Eva Bagyinszky & Vo Van Giau

  2. Department of Neurology, Inha University School of Medicine, Incheon, Republic of Korea

    Seong Hye Choi

  3. Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seoul, Republic of Korea

    Sang Yun Kim

  4. Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, Qingdao University, Qingdao, China

    Lingyan Shen

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  1. Lingyan Shen
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Correspondence to Vo Van Giau or Seong Hye Choi.

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Conflict of Interest

Lingyan Shen, Seong Soo A. An, Eva Bagyinszky, Vo Van Giau, Seong Hye Choi, SangYun Kim declares that they have no conflicts of interest.

Human and animal rights

All human DNA samples were approved by the Institutional Review Board of the Seoul National University Bundang Hospital and Inha University Hospital.

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Shen, L., An, S.S.A., Bagyinszky, E. et al. Novel GRN mutations in Koreans with Alzheimer’s disease. Mol. Cell. Toxicol. 15, 345–352 (2019). https://doi.org/10.1007/s13273-019-0038-4

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  • DOI: https://doi.org/10.1007/s13273-019-0038-4

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