A novel PSEN2 p.Ser175Phe variant in a family with Alzheimer's disease

Topic: Genetics and APOE

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.

Key findings

• So far, autosomal dominantly inherited mutations in "Presenilin 1" (PSEN1), "Presenilin 2" (PSEN2), and "Amyloid precursor protein" (APP) genes were associated with familial AD.
• 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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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1007/s10072-021-05243-w
• PubMed: 33855622
• Original source →

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@article{guven2021-33855622,
  author  = {Guven, Gamze and Samanci, Bedia and Gulec, Cagri and Hanagasi, Hasmet and Gurvit, Hakan and Gokalp, Ebru Erzurumluoglu and Tepgec, Fatih and Guler, Suleyman and others},
  title   = {{A novel PSEN2 p.Ser175Phe variant in a family with Alzheimer's disease}},
  journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
  year    = {2021},
  doi     = {10.1007/s10072-021-05243-w},
  pmid    = {33855622},
  url     = {https://doi.org/10.1007/s10072-021-05243-w}
}

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