Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2018 Jul 31;13:1321-1329.
doi: 10.2147/CIA.S170374. eCollection 2018.

A Pathogenic PSEN2 p.His169Asn Mutation Associated With Early-Onset Alzheimer's Disease

Free PMC article
Case Reports

A Pathogenic PSEN2 p.His169Asn Mutation Associated With Early-Onset Alzheimer's Disease

Vo Van Giau et al. Clin Interv Aging. .
Free PMC article


Background: Autosomal dominant early-onset Alzheimer's disease (EOAD) is genetically heterogeneous and has been associated with mutations in 3 different genes, coding for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). Most frequent cases are associated with mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare.

Methods: Patient who presented progressive memory decline in her 50s was enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. Genetic tests were performed in the patient to evaluate possible mutations using next-generation sequencing (NGS). The pathogenic nature of missense mutation and its 3D protein structure prediction were performed by in silico prediction programs.

Results: A pathogenic mutation in the PSEN2 gene in a Korean patient associated with EOAD was identified. Targeted Next-generation sequencing and Sanger sequencing revealed a heterozygous C to A transition at position 505 (c.505C>A), resulting in a probably missense mutation at codon 169 (p.His169Asn) in PSEN2. PolyPhen-2 and SIFT software analyses predicted this mutation to be a probable damaging variant. This hypothesis was supported by the results of 3D in silico modelling analyses that predicted the p.His169Asn may result in major helix torsion due to histidine to asparagine substitution. Mutation may cause additional stresses with hydrophobic residues on the surface that interact inside the transmembrane domain III, which is a conserved domain in PSEN2 His169.

Conclusion: These findings revealed that the p.His169Asn might be an important residue in PSEN2, which may alter the functions of PSEN2, suggesting its potential involvement with AD phenotype. Future functional studies are needed to evaluate the role of PSEN2 p.His169Asn mutation in AD disease progression.

Keywords: Alzheimer’s disease; next-generation sequencing; p.His169Asn mutation; presenilin-2.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.


Figure 1
Figure 1
Brain structural neuroimaging data and family pedigree of the proband at diagnosis. Note: (A) Axial FLAIR, coronal, and sagittal T1 images of brain MRI, arrows pointing at left-dominant bilateral temporal lobe atrophy, (B) FDG-PET, arrows pointing at hypometabolism in left temporal cortex, right anterior temporal cortex and bilateral frontal cortex and (C) family tree identifying the proband (II-4) with the PSEN2 p.His169Asn. Abbreviations: FDG-PET, 18 F-fludeoxyglucose positron emission tomography; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; PSEN, presenilin.
Figure 2
Figure 2
Identification and in silico analysis of function the mutation in the patient. Notes: (A) NGS and Sanger sequencing data identifying the PSEN2 H169N mutation in the proband. (B) Bulkiness profile of wild-type and H169N mutant PSEN2 proteins. Dotted line represents the shift in the bulkiness around the mutant site. X-axis represents amino acid sequence from N- to C-terminal. Y-axis represents scores computed by each algorithm. The prediction was done using the ProtScale program at Expasy server. (C) Differences of normal and mutant PSEN2 have been highlighted with a black circle, and histidine was labeled yellow, while asparagine was labeled pink. (D) ClueGO model on the putative pathways on proteins which carried mutations. Abbreviations: NGS, next-generations sequencing; PSEN, presenilin.

Similar articles

See all similar articles

Cited by 5 articles


    1. Rosenberg RN. The molecular and genetic basis of AD: the end of the beginning. Neurology. 2000;54:2045–2054. - PubMed
    1. Brouwers N, Sleegers K, Van Broeckhoven C. Molecular genetics of Alzheimer’s disease: an update. Ann Med. 2008;40(8):562–583. - PubMed
    1. Cacace R, Sleegers K, Van Broeckhoven C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement. 2016;12(6):733–748. - PubMed
    1. Portet F, Dauvilliers YD, Campion G, et al. Very early onset AD with a de novo mutation in the presenilin 1 gene (Met 233 Leu) Neurology. 2003;61(8):1136–1137. - PubMed
    1. Golan MP, Styczynska M, Jozwiak K, et al. Early-onset Alzheimer’s disease with a de novo mutation in the presenilin 1 gene. Exp Neurol. 2007;208(2):264–268. - PubMed

Publication types