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Int. J. Mol. Sci. 2018, 19(9), 2604;

PSEN1 p.Thr116Ile Variant in Two Korean Families with Young Onset Alzheimer’s Disease

Department of Bionano Technology, Gachon University, Sungnam 13120, Korea
Department of Neurology, Korea University Guro Hosipital, Korea University, Seoul 08308, Korea
Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University, Seoul 07985, Korea
Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Sungnam 13620, Korea
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 3 August 2018 / Revised: 28 August 2018 / Accepted: 29 August 2018 / Published: 2 September 2018
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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An in depth study of PSEN1 mutation p.Thr116Ile (c.335C>T) is presented from two Korean families with autosomal dominant inheritance. Clinical manifestation of our patients included memory loss, attention deficits, visuospatial dysfunction, agnosia, aphasia, apraxia, and personality changes, which occurred in their 30s. PSEN1 Thr116Ile was initially discovered in an Italian patient and two French families with early onset Alzheimer’s disease (EOAD) with similar age of onset. To verify the possible pathogenic mechanisms of mutation, in silico predictions and 3D modeling were performed. Structure predictions revealed significant aberrations in first hydrophilic loop (HL-I loop). The hydrophobic isoleucine could alter the loop orientation through increased hydrophobic contacts with the surrounding amino acids. Mutation could destroy a possible hydrogen bond between tyrosine 115 and threonine 116, which may affect the loop conformation. HL-I was confirmed as a conservative region of PSEN1, which may be critical in PSEN1 functions. An additional pathogenic mutation, PSEN1 Thr116Asn, was also found for the same residue, where the patient presented young onset AD (YOND). Other mutations in HL-I loop, such as Tyr115His and Glu120Asp, were described in patients with YOND, supporting the critical role of HL-I loop in PSEN1 activity. View Full-Text
Keywords: young onset Alzheimer’s dementia; familial; presenilin-1; mutation; PSEN1 Thr116Ile mutation young onset Alzheimer’s dementia; familial; presenilin-1; mutation; PSEN1 Thr116Ile mutation

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Bagyinszky, E.; Lee, H.-M.; Van Giau, V.; Koh, S.-B.; Jeong, J.H.; An, S.S.A.; Kim, S. PSEN1 p.Thr116Ile Variant in Two Korean Families with Young Onset Alzheimer’s Disease. Int. J. Mol. Sci. 2018, 19, 2604.

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