PSEN1 p. Thr116Ile Variant in Two Korean Families with Young Onset Alzheimer's Disease
- 주제(키워드) young onset Alzheimer's dementia , familial , presenilin-1 , mutation , PSEN1 Thr116Ile mutation
- 주제(기타) Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
- 설명문(일반) [Bagyinszky, Eva; Giau, Vo Van; An, Seong Soo A.] Gachon Univ, Dept Bionano Technol, Sungnam 13120, South Korea; [Lee, Hye-Mi; Koh, Seong-Beom] Korea Univ, Guro Hosp, Dept Neurol, Seoul 08308, South Korea; [Jeong, Jee Hyang] Ewha Womans Univ, Mokdong Hosp, Dept Neurol, Seoul 07985, South Korea; [Kim, SangYun] Seoul Natl Univ, Dept Neurol, Coll Med, Sungnam 13620, South Korea; [Kim, SangYun] Seoul Natl Univ, Bundang Hosp, Neurocognit Behav Ctr, Sungnam 13620, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 MDPI
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000156158
- 본문언어 영어
- Published As http://dx.doi.org/10.3390/ijms19092604
초록/요약
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.
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