A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer’s disease

A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer’s disease

Vo Van Giau,1,* Jung-Min Pyun,2,* Eva Bagyinszky,2 Seong Soo A An,1 SangYun Kim2 1Department of BioNano Technology, Gachon Medical Research Institute, Gachon University, Seongnam, South Korea; 2Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior...

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Autores principales: Giau VV, Pyun JM, Bagyinszky E, An SSA, Kim SY
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2018
Materias:
Alzheimer’s disease
p.His169Asn mutation
presenilin-2
next generation sequencing.
Geriatrics
RC952-954.6
Acceso en línea:https://doaj.org/article/e5a1fa85e0da44dd939b077609e10873
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spelling oai:doaj.org-article:e5a1fa85e0da44dd939b077609e108732021-12-02T06:04:59ZA pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer’s disease1178-1998https://doaj.org/article/e5a1fa85e0da44dd939b077609e108732018-07-01T00:00:00Zhttps://www.dovepress.com/a-pathogenic-psen2-phis169asn-mutation-associated-with-early-onset-alz-peer-reviewed-article-CIAhttps://doaj.org/toc/1178-1998Vo Van Giau,1,* Jung-Min Pyun,2,* Eva Bagyinszky,2 Seong Soo A An,1 SangYun Kim2 1Department of BioNano Technology, Gachon Medical Research Institute, Gachon University, Seongnam, South Korea; 2Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea *These authors contributed equally to this work 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, p.His169Asn mutation, presenilin-2, next-generation sequencingGiau VVPyun JMBagyinszky EAn SSAKim SYDove Medical PressarticleAlzheimer’s diseasep.His169Asn mutationpresenilin-2next generation sequencing.GeriatricsRC952-954.6ENClinical Interventions in Aging, Vol Volume 13, Pp 1321-1329 (2018)
institution DOAJ
collection DOAJ
language EN
topic Alzheimer’s disease
p.His169Asn mutation
presenilin-2
next generation sequencing.
Geriatrics
RC952-954.6
spellingShingle Alzheimer’s disease
p.His169Asn mutation
presenilin-2
next generation sequencing.
Geriatrics
RC952-954.6
Giau VV
Pyun JM
Bagyinszky E
An SSA
Kim SY
A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer’s disease
description Vo Van Giau,1,* Jung-Min Pyun,2,* Eva Bagyinszky,2 Seong Soo A An,1 SangYun Kim2 1Department of BioNano Technology, Gachon Medical Research Institute, Gachon University, Seongnam, South Korea; 2Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea *These authors contributed equally to this work 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, p.His169Asn mutation, presenilin-2, next-generation sequencing
format article
author Giau VV
Pyun JM
Bagyinszky E
An SSA
Kim SY
author_facet Giau VV
Pyun JM
Bagyinszky E
An SSA
Kim SY
author_sort Giau VV
title A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer’s disease
title_short A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer’s disease
title_full A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer’s disease
title_fullStr A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer’s disease
title_full_unstemmed A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer’s disease
title_sort pathogenic psen2 p.his169asn mutation associated with early-onset alzheimer’s disease
publisher Dove Medical Press
publishDate 2018
url https://doaj.org/article/e5a1fa85e0da44dd939b077609e10873
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