{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T21:40:26Z","timestamp":1791668426449,"version":"4.3.4"},"reference-count":27,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF)","award":["2021R1A6A1A03038996"],"award-info":[{"award-number":["2021R1A6A1A03038996"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["VHSM21041"],"award-info":[{"award-number":["VHSM21041"]}]},{"name":"VHS Medical Center research grant, Republic of Korea","award":["2021R1A6A1A03038996"],"award-info":[{"award-number":["2021R1A6A1A03038996"]}]},{"name":"VHS Medical Center research grant, Republic of Korea","award":["VHSM21041"],"award-info":[{"award-number":["VHSM21041"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The etiology of early-onset Alzheimer\u2019s disease (EOAD) is associated with alterations in the production of amyloid beta (A\u03b2) species caused by mutations in the APP, PSEN1, and PSEN2 genes. Mutations affect intra- or inter-molecular interactions and processes between the \u03b3-secretase complex and amyloid precursor protein (APP), leading to the aberrant sequential cleavage of A\u03b2 species. A 64-year-old woman presented with progressive memory decline, mild right hippocampal atrophy, and a family history of Alzheimer\u2019s dementia (AD). Whole exome sequencing was performed to evaluate AD-related gene mutations, which were verified by Sanger sequencing. A mutation-caused structural alteration of APP was predicted using in silico prediction programs. Two AD-related mutations, in APP (rs761339914; c.G1651A; p.V551M) and PSEN2 (rs533813519; c.C505A; p.H169N), were identified. The APP Val551Met mutation in the E2 domain may influence APP homodimerization through changes in intramolecular interactions between adjacent amino acids, altering A\u03b2 production. The second mutation was PSEN2 His169Asn mutation, which was previously reported in five EOAD patients from Korea and China, with a relatively high frequency in the East Asian population. According to a previous report, the presenilin 2 protein was predicted to result in a major helical torsion by PSEN2 His169Asn mutation. Notably, the co-existence of APP Val551Met and PSEN2 His169Asn may induce a synergistic effect by both mutations. Future functional studies are needed to clarify the pathological effects of these double mutations.<\/jats:p>","DOI":"10.3390\/ijms24087446","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T01:39:05Z","timestamp":1681868345000},"page":"7446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Double Mutations in a Patient with Early-Onset Alzheimer\u2019s Disease in Korea: An APP Val551Met and a PSEN2 His169Asn"],"prefix":"10.3390","volume":"24","author":[{"given":"Heewon","family":"Bae","sequence":"first","affiliation":[{"name":"Department of Neurology, Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul 05368, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5402-337X","authenticated-orcid":false,"given":"Kyu Hwan","family":"Shim","sequence":"additional","affiliation":[{"name":"Department of Bionano Technology, Gachon University, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4664-4904","authenticated-orcid":false,"given":"Jang","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Veterans Health Service Medical Center, Seoul 05368, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2448-2599","authenticated-orcid":false,"given":"Young-Soon","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Soonchunhyang University College of Medicine, Cheonan Hospital, Cheonan 31151, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-6183","authenticated-orcid":false,"given":"Seong Soo A.","family":"An","sequence":"additional","affiliation":[{"name":"Department of Bionano Technology, Gachon University, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Ju","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul 05368, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ayodele, T., Rogaeva, E., Kurup, J.T., Beecham, G., and Reitz, C. (2021). Early-Onset Alzheimer\u2019s Disease: What Is Missing in Research?. Curr. Neurol. Neurosci. Rep., 21.","DOI":"10.1007\/s11910-020-01090-y"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12017-009-8104-z","article-title":"An overview of APP processing enzymes and products","volume":"12","author":"Chow","year":"2010","journal-title":"Neuromol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12787","DOI":"10.1523\/JNEUROSCI.3657-09.2009","article-title":"The \u03b2-Secretase Enzyme BACE in Health and Alzheimer\u2019s Disease: Regulation, Cell Biology, Function, and Therapeutic Potential","volume":"29","author":"Vassar","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1038\/nm1295-1291","article-title":"The Swedish mutation causes early-onset Alzheimer\u2019s disease by \u03b2-secretase cleavage within the secretory pathway","volume":"1","author":"Haass","year":"1995","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1073\/pnas.032395699","article-title":"The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain","volume":"99","author":"Lichtenthaler","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0896-6273(03)00205-8","article-title":"Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active \u03b3-Secretase Complex","volume":"38","year":"2003","journal-title":"Neuron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.cell.2017.07.004","article-title":"Alzheimer\u2019s-Causing Mutations Shift A\u03b2 Length by Destabilizing \u03b3-Secretase-A\u03b2n Interactions","volume":"170","author":"Szaruga","year":"2017","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1083\/jcb.147.2.277","article-title":"Presenilin 1 Controls \u03b3-Secretase Processing of Amyloid Precursor Protein in Pre-Golgi Compartments of Hippocampal Neurons","volume":"147","author":"Annaert","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Giau, V.V., Bagyinszky, E., Youn, Y.C., An, S.S.A., and Kim, S. (2019). APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194757"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dai, M.-H., Zheng, H., Zeng, L.-D., and Zhang, Y. (2018). The genes associated with early-onset Alzheimer\u2019s disease. Oncotarget, 9.","DOI":"10.18632\/oncotarget.23738"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.2147\/CIA.S170374","article-title":"A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer\u2019s disease","volume":"13","author":"Giau","year":"2018","journal-title":"Clin. Interv. Aging"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1159\/000366272","article-title":"Clinical and Neuroimaging Characterization of Chinese Dementia Patients with PSEN1 and PSEN2 Mutations","volume":"39","author":"Shi","year":"2015","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"696","DOI":"10.14336\/AD.2018.0208","article-title":"The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia","volume":"9","author":"Xu","year":"2018","journal-title":"Aging Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ma, L., Zhang, J., Shi, Y., Wang, W., Ren, Z., Xia, M., Zhang, Y., and Yang, M. (2019). Gene mutations in a Han Chinese Alzheimer\u2019s disease cohort. Brain Behav., 9.","DOI":"10.1002\/brb3.1180"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hsu, S., Pimenova, A.A., Hayes, K., Villa, J.A., Rosene, M.J., Jere, M., Goate, A.M., and Karch, C.M. (2020). Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol. Dis., 139.","DOI":"10.1016\/j.nbd.2020.104817"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.jpsychires.2019.03.026","article-title":"Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer\u2019s disease","volume":"113","author":"Wang","year":"2019","journal-title":"J. Psychiatr. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3233\/JAD-180415","article-title":"Genetic Study of Alzheimer\u2019s Disease in Saudi Population","volume":"67","author":"Qadi","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2422.e13","DOI":"10.1016\/j.neurobiolaging.2014.04.026","article-title":"Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer\u2019s disease","volume":"35","author":"Sassi","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2881.e1","DOI":"10.1016\/j.neurobiolaging.2014.06.002","article-title":"Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer\u2019s disease","volume":"35","author":"Sassi","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1038\/ejhg.2014.300","article-title":"Rare variants in \u03b2-Amyloid precursor protein (APP) and Parkinson\u2019s disease","volume":"23","author":"Schulte","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/j.jalz.2015.02.007","article-title":"On the identification of low allele frequency mosaic mutations in the brains of Alzheimer\u2019s disease patients","volume":"11","author":"Lau","year":"2015","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5453","DOI":"10.1021\/bi101846x","article-title":"The E2 Domains of APP and APLP1 Share a Conserved Mode of Dimerization","volume":"50","author":"Lee","year":"2011","journal-title":"Biochemistry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"33923","DOI":"10.1074\/jbc.M105410200","article-title":"Homodimerization of Amyloid Precursor Protein and Its Implication in the Amyloidogenic Pathway of Alzheimer\u2019s Disease","volume":"276","author":"Scheuermann","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15016","DOI":"10.1074\/jbc.M808755200","article-title":"Neuroprotective Secreted Amyloid Precursor Protein Acts by Disrupting Amyloid Precursor Protein Dimers","volume":"284","author":"Gralle","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lewis, C.M., and Vassos, E. (2020). Polygenic risk scores: From research tools to clinical instruments. Genome Med., 12.","DOI":"10.1186\/s13073-020-00742-5"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lali, R., Chong, M., Omidi, A., Mohammadi-Shemirani, P., Le, A., Cui, E., and Par\u00e9, G. (2021). Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories. Nat. Commun., 12.","DOI":"10.1038\/s41467-021-26114-0"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7446\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:18:10Z","timestamp":1760123890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,18]]},"references-count":27,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24087446"],"URL":"https:\/\/doi.org\/10.3390\/ijms24087446","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,18]]}}}