Abstract
Alzheimer’s disease (AD) can be either sporadic or familial, and familial forms of AD accounts for only 5% of the cases. So far, autosomal dominantly inherited mutations in “Presenilin 1” (PSEN1), “Presenilin 2” (PSEN2), and “Amyloid precursor protein” (APP) genes were associated with familial AD. Amid the others, pathogenic mutations in the PSEN2 gene are less common. In this study, we describe a novel heterozygous PSEN2 (c.524C>T, p.Ser175Phe) alteration identified in a 58-year-old Turkish patient from a family with multiple dementia cases. This variant was further present in the patient’s clinically affected maternal cousin as well as in the asymptomatic mother and two maternal aunts who were carriers of the APOE ε2/ε3 genotype. The variant is located in the conserved residue of transmembrane domain III encoded by exon 6 of the major transcript. In silico protein structure analyses predicted that this variant might change the architecture of interaction between the two alpha helixes of PSEN2. We propose that p.Ser175Phe may have a pathogenic effect on protein function and may play a significant role in the molecular pathways leading to Alzheimer’s disease in this family.
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Acknowledgements
The authors would like to thank the family for their generous participation. The authors also thank Cagla Donmez, Rukiye Aslan, and Utku Uyan for their help in obtaining the samples. We would also like to acknowledge Khusan Khodzhaev, for technical assistance towards the construction of the artwork. This research did not receive any specific grant from funding agencies in the public, commercial, or not for profit sectors.
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Supplementary Fig. 1.
Sanger sequencing chromatograms showing the PSEN2 p.Ser175Phe mutation site in family members. (PDF 4332 kb)
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Guven, G., Samanci, B., Gulec, C. et al. A novel PSEN2 p.Ser175Phe variant in a family with Alzheimer’s disease. Neurol Sci 42, 2497–2504 (2021). https://doi.org/10.1007/s10072-021-05243-w
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DOI: https://doi.org/10.1007/s10072-021-05243-w