Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family

Gaik-Siew Ch’ng,1,* Seong Soo A An,2,* Sun Oh Bae,2 Eva Bagyinszky,2 SangYun Kim3,41Department of Genetics, Kuala Lumpur Hospital, Malaysia; 2Department of Bionano Technology, Gachon University, 3Department of Neurology, Seoul National University College of Medicine, 4Seoul Nation...

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Autores principales:	Ch’ng GS, An SSA, Bae SO, Bagyinszky E, Kim SY
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2015
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/87dc9a1cbf9e44f98c0358bc0cdc0cd9
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spelling	oai:doaj.org-article:87dc9a1cbf9e44f98c0358bc0cdc0cd92021-12-02T03:42:15ZIdentification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family1178-2021https://doaj.org/article/87dc9a1cbf9e44f98c0358bc0cdc0cd92015-09-01T00:00:00Zhttps://www.dovepress.com/identification-of-two-novel-mutations-psen1-e280k-and-prnp-g127s-in-a--peer-reviewed-article-NDThttps://doaj.org/toc/1178-2021Gaik-Siew Ch’ng,1,* Seong Soo A An,2,* Sun Oh Bae,2 Eva Bagyinszky,2 SangYun Kim3,41Department of Genetics, Kuala Lumpur Hospital, Malaysia; 2Department of Bionano Technology, Gachon University, 3Department of Neurology, Seoul National University College of Medicine, 4Seoul National University Bundang Hospital, South Korea*These authors contributed equally to this workAbstract: Alzheimer’s disease (AD) is the most common form of dementia, which can be categorized into two main forms: early onset AD and late onset AD. The genetic background of early onset AD is well understood, and three genes, the APP, PSEN1, and PSEN2 have been identified as causative genes. In the current study, we tested three siblings from Malaysia who were diagnosed with early onset dementia, as well as their available family members. The family history was positive as their deceased father was similarly affected. Patients were tested for mutations in APP, PSEN1, PSEN2, and PRNP. A novel variant, E280K, was discovered in exon 8 of PSEN1 in the three siblings. In silico analyses with SIFT, SNAP, and PolyPhen2 prediction tools and three-dimensional modeling were performed, and the results suggested that the mutation is probably a pathogenic variant. Two additional pathogenic mutations were previously been described for codon 280, E280A, and E280G, which could support the importance of the E280 residue in the PS1 protein contributing to the pathogenic nature of E280K. Additional ten family members were screened for the E280K mutation, and all of them were negative. Six of them presented with a variety of neuropsychiatric symptoms, including learning disabilities, epilepsy, and schizophrenia, while four family members were asymptomatic. A novel PRNP G127S mutation was found in a step-niece of the three siblings harboring the PSEN1 E280K mutation. In silico predictions for PRNP G127S mutation suggested that this might be possibly a damaging variant. Additional studies to characterize PRNP G127S would be necessary to further understand the effects of this mutation. Keywords: Alzheimer’s disease, presenilin-1, prion, mutationCh’ng GSAn SSABae SOBagyinszky EKim SYDove Medical PressarticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENNeuropsychiatric Disease and Treatment, Vol 2015, Iss default, Pp 2315-2322 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Ch’ng GS An SSA Bae SO Bagyinszky E Kim SY Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family
description	Gaik-Siew Ch’ng,1,* Seong Soo A An,2,* Sun Oh Bae,2 Eva Bagyinszky,2 SangYun Kim3,41Department of Genetics, Kuala Lumpur Hospital, Malaysia; 2Department of Bionano Technology, Gachon University, 3Department of Neurology, Seoul National University College of Medicine, 4Seoul National University Bundang Hospital, South Korea*These authors contributed equally to this workAbstract: Alzheimer’s disease (AD) is the most common form of dementia, which can be categorized into two main forms: early onset AD and late onset AD. The genetic background of early onset AD is well understood, and three genes, the APP, PSEN1, and PSEN2 have been identified as causative genes. In the current study, we tested three siblings from Malaysia who were diagnosed with early onset dementia, as well as their available family members. The family history was positive as their deceased father was similarly affected. Patients were tested for mutations in APP, PSEN1, PSEN2, and PRNP. A novel variant, E280K, was discovered in exon 8 of PSEN1 in the three siblings. In silico analyses with SIFT, SNAP, and PolyPhen2 prediction tools and three-dimensional modeling were performed, and the results suggested that the mutation is probably a pathogenic variant. Two additional pathogenic mutations were previously been described for codon 280, E280A, and E280G, which could support the importance of the E280 residue in the PS1 protein contributing to the pathogenic nature of E280K. Additional ten family members were screened for the E280K mutation, and all of them were negative. Six of them presented with a variety of neuropsychiatric symptoms, including learning disabilities, epilepsy, and schizophrenia, while four family members were asymptomatic. A novel PRNP G127S mutation was found in a step-niece of the three siblings harboring the PSEN1 E280K mutation. In silico predictions for PRNP G127S mutation suggested that this might be possibly a damaging variant. Additional studies to characterize PRNP G127S would be necessary to further understand the effects of this mutation. Keywords: Alzheimer’s disease, presenilin-1, prion, mutation
format	article
author	Ch’ng GS An SSA Bae SO Bagyinszky E Kim SY
author_facet	Ch’ng GS An SSA Bae SO Bagyinszky E Kim SY
author_sort	Ch’ng GS
title	Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family
title_short	Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family
title_full	Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family
title_fullStr	Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family
title_full_unstemmed	Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family
title_sort	identification of two novel mutations, psen1 e280k and prnp g127s, in a malaysian family
publisher	Dove Medical Press
publishDate	2015
url	https://doaj.org/article/87dc9a1cbf9e44f98c0358bc0cdc0cd9
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Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family

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