{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:04:30Z","timestamp":1790712270129,"version":"4.1.0"},"reference-count":123,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T00:00:00Z","timestamp":1683504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education","award":["NRF-2020R1A2B5B01002463"],"award-info":[{"award-number":["NRF-2020R1A2B5B01002463"]}]},{"name":"Ministry of Education","award":["2021R1A6A1A03038996"],"award-info":[{"award-number":["2021R1A6A1A03038996"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer\u2019s disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson\u2019s disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and\/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes.<\/jats:p>","DOI":"10.3390\/ijms24098417","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T03:34:53Z","timestamp":1683516893000},"page":"8417","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2448-2599","authenticated-orcid":false,"given":"Youngsoon","family":"Yang","sequence":"first","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\/0000-0002-0487-8668","authenticated-orcid":false,"given":"Eva","family":"Bagyinszky","sequence":"additional","affiliation":[{"name":"Graduate School of Environment Department of Industrial and Environmental Engineering, Gachon University, Seongnam 13120, 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"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3233\/JAD-2006-102-312","article-title":"Presenilin structure in mechanisms leading to Alzheimer\u2019s disease","volume":"10","author":"Dewji","year":"2006","journal-title":"J. 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