{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:33:03Z","timestamp":1791952383141,"version":"4.3.4"},"reference-count":34,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:00:00Z","timestamp":1633651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Presenilin-1 (PSEN1) is one of the causative genes for early onset Alzheimer\u2019s disease (EOAD). Recently, emerging studies have reported several novel PSEN1 mutations among Asians. In this study, a PSEN1 Val96Phe mutation was discovered in two siblings from Malaysia with a strong family history of disease. This is the second report of PSEN1 Val96Phe mutation among EOAD patients in Asia and in the world. Patients presented symptomatic changes in their behaviors and personality, such as apathy and withdrawal in their 40s. Previous cellular studies with COS1 cell lines revealed the mutation increased the amyloid-\u03b242 (A\u03b242) productions. In the present study, whole-exome sequencing was performed on the two siblings with EOAD, and they were analyzed against the virtual panel of 100 genes from various neurodegenerative diseases. In silico modeling was also performed on PSEN1 Val96Phe mutation. This mutation was located on the first transmembrane helix of PSEN1 protein, resulting significant intramolecular stresses in the helices. This helical domain would play a significant role in \u03b3-secretase cleavage for the increased A\u03b242 productions. Several other adjacent mutations were reported in this helical domain, including Ile83Thr or Val89Leu. Our study suggested that perturbations in TMI-HLI-TMII regions could also be associated with C-terminal fragment accumulation of APP and enhanced amyloid productions.<\/jats:p>","DOI":"10.3390\/brainsci11101328","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T23:37:08Z","timestamp":1633822628000},"page":"1328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0487-8668","authenticated-orcid":false,"given":"Eva","family":"Bagyinszky","sequence":"first","affiliation":[{"name":"Department of Industrial and Environmental Engineering, Graduate School of Environment, Gachon University, Seongnam 13120, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7595-1618","authenticated-orcid":false,"given":"Gaik-Siew","family":"Ch\u2019ng","sequence":"additional","affiliation":[{"name":"Department of Genetics, Penang Hospital, Penang 10990, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Yan","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur 50586, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Soo A.","family":"An","sequence":"additional","affiliation":[{"name":"Department of Bionano Technology, Gachon University, Seongnam 13120, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SangYun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam 13620, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/S1474-4422(16)30275-7","article-title":"Clinical heterogeneity in familial Alzheimer\u2019s disease","volume":"15","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1212\/WNL.0000000000000596","article-title":"Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis","volume":"83","author":"Ryman","year":"2014","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0896-6273(00)80230-5","article-title":"Familial Alzheimer\u2019s disease-linked presenilin 1 variants elevate Abeta1-42\/1-40 ratio in vitro and in vivo","volume":"17","author":"Borchelt","year":"1996","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"535","DOI":"10.2147\/CIA.S51571","article-title":"The genetics of Alzheimer\u2019s disease","volume":"9","author":"Bagyinszky","year":"2014","journal-title":"Clin. 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