{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:10:30Z","timestamp":1792789830220,"version":"4.5.0"},"reference-count":26,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T00:00:00Z","timestamp":1655164800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2022,6,14]]},"abstract":"<jats:p>Background: The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1%,Alzheimer\u2019s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common. Objective: With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients. Methods: 702 AD participants, aged 30\u201385, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT\/MRI, and next-generation DNA sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations. Results: Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher A\u03b242 and A\u03b242\/A\u03b240 levels relative to the wild-type PSEN2. The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter A\u03b242, A\u03b240 levels, or A\u03b242\/A\u03b240 ratio. 1.9%,(13\/702) subjects harbored rare PSEN2 variants. 0.4%,(3\/702) subjects carried pathogenic\/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization. Conclusion: The PSEN2 N141S, M239T, and I368F are functionally validated mutations.<\/jats:p>","DOI":"10.3233\/jad-220194","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T14:01:40Z","timestamp":1650981700000},"page":"1549-1556","source":"Crossref","is-referenced-by-count":8,"title":["PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer\u2019s Disease: Data from PUMCH Dementia Cohort"],"prefix":"10.1177","volume":"87","author":[{"given":"Liling","family":"Dong","sequence":"first","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longze","family":"Sha","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhui","family":"Mao","sequence":"additional","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Huang","sequence":"additional","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Chu","sequence":"additional","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Peng","sequence":"additional","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Cui","sequence":"additional","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Gao","sequence":"additional","affiliation":[{"name":"Neurology Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-220194_ref1","doi-asserted-by":"crossref","first-page":"15132","DOI":"10.18632\/oncotarget.23738","article-title":"The genes associated with early-onset Alzheimer\u2019s disease","volume":"9","author":"Dai","year":"2018","journal-title":"Oncotarget"},{"key":"10.3233\/JAD-220194_ref2","doi-asserted-by":"crossref","first-page":"8208","DOI":"10.1073\/pnas.94.15.8208","article-title":"Interaction between amyloid precursor protein and presenilins in mammalian cells: Implications for the pathogenesis of Alzheimer disease","volume":"94","author":"Xia","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.3233\/JAD-220194_ref3","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/j.1471-4159.2004.02858.x","article-title":"Presenilin 2 familial Alzheimer\u2019s disease mutations result in partial loss of function and dramatic changes in Abeta 42\/40 ratios","volume":"92","author":"Walker","year":"2005","journal-title":"J Neurochem"},{"key":"10.3233\/JAD-220194_ref4","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The diagnosis of dementia due to Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"McKhann","year":"2011","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-220194_ref5","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/geront\/9.3_Part_1.179","article-title":"Assessment of older people: Self-maintaining and instrumental activities of daily living","volume":"9","author":"Lawton","year":"1969","journal-title":"Gerontologist"},{"issue":"(Suppl)","key":"10.3233\/JAD-220194_ref6","first-page":"5","article-title":"Activities of daily living scale: Questionnaire and application instructions","author":"Zhang","year":"1995","journal-title":"Shanghai Arch Psychiatry"},{"key":"10.3233\/JAD-220194_ref7","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"Li","year":"2010","journal-title":"Bioinformatics"},{"key":"10.3233\/JAD-220194_ref8","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"10.3233\/JAD-220194_ref9","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"10.3233\/JAD-220194_ref10","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2147\/CIA.S128884","article-title":"A case of possibly pathogenic PSEN2 R62C mutation in a patient with probable early-onset Alzheimer\u2019s dementia supported by structure prediction","volume":"12","author":"Park","year":"2017","journal-title":"Clin Interv Aging"},{"key":"10.3233\/JAD-220194_ref11","doi-asserted-by":"crossref","first-page":"265","DOI":"10.2174\/1567205018666210608120339","article-title":"Clinical phenotype and mutation of lzheimer\u2019s disease with causative genetic mutation spectrum in a Chinese cohort","volume":"18","author":"Mao","year":"2021","journal-title":"Curr lzheimer Res"},{"key":"10.3233\/JAD-220194_ref12","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.neubiorev.2014.02.010","article-title":"Familial Alzheimer\u2019s disease sustained by presenilin 2 mutations: Systematic review of literature and genotype-phenotype correlation","volume":"42","author":"Canevelli","year":"2014","journal-title":"Neurosci Biobehav Rev"},{"key":"10.3233\/JAD-220194_ref13","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1159\/000094972","article-title":"Cognitive deficits in familial Alzheimer\u2019s disease associated with M239V mutation of presenilin 2","volume":"22","author":"Giovagnoli","year":"2006","journal-title":"Dement Geriatr Cogn Discord"},{"key":"10.3233\/JAD-220194_ref14","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1080\/07853890802186905","article-title":"Molecular genetics of Alzheimer\u2019s disease: An update","volume":"40","author":"Brouwers","year":"2008","journal-title":"Ann Med"},{"key":"10.3233\/JAD-220194_ref15","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/alz.12005","article-title":"PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer\u2019s disease","volume":"16","author":"Jia","year":"2020","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-220194_ref16","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/j.1749-6632.2000.tb06910.x","article-title":"High frequency of mutations in four different disease genes in early-onset dementia","volume":"920","author":"Finckh","year":"2000","journal-title":"Ann N Y Acad Sci"},{"key":"10.3233\/JAD-220194_ref17","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":"10.3233\/JAD-220194_ref18","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1016\/j.neurobiolaging.2014.04.011","article-title":"Novel mutation in the PSEN2 gene (N141Y) associated with early-onset autosomal dominant Alzheimer\u2019s disease in a Chinese Han family","volume":"35","author":"Niu","year":"2014","journal-title":"Neurobiol Aging"},{"key":"10.3233\/JAD-220194_ref19","first-page":"189","article-title":"Early-onset familial Alzheimer\u2019s disease in a family with mutation of presenilin 2 gene","volume":"46","author":"Li","year":"2021","journal-title":"Zhong Nan Da Xue Xue Bao Yi Xue Ban"},{"key":"10.3233\/JAD-220194_ref20","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3233\/JAD-2010-1369","article-title":"A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer\u2019s disease","volume":"20","author":"Piscopo","year":"2010","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-220194_ref21","doi-asserted-by":"crossref","first-page":"509","DOI":"10.3233\/JAD-2009-0986","article-title":"A novel Italian presenilin 2 gene mutation with prevalent behavioral phenotype","volume":"16","author":"Marcon","year":"2009","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-220194_ref22","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1001\/archneur.60.8.1149","article-title":"A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease","volume":"60","author":"Ezquerra","year":"2003","journal-title":"Arch Neurol"},{"key":"10.3233\/JAD-220194_ref23","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1097\/WAD.0000000000000438","article-title":"Novel PSEN1 and PSEN2 mutations identified in sporadic early-onset Alzheimer disease and posterior cortical atrophy","volume":"35","author":"Li","year":"2021","journal-title":"Alzheimer Dis Assoc Disord"},{"key":"10.3233\/JAD-220194_ref24","doi-asserted-by":"crossref","unstructured":"Husain M , Schott JM (2016) Oxford textbook of cognitive neurology and dementia. Oxford University Press, Oxford .","DOI":"10.1093\/med\/9780199655946.001.0001"},{"key":"10.3233\/JAD-220194_ref25","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1212\/WNL.0b013e3181bd8271","article-title":"CSF biomarkers predict rate of cognitive decline in Alzheimer disease","volume":"73","author":"Kester","year":"2009","journal-title":"Neurology"},{"key":"10.3233\/JAD-220194_ref26","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/nn0901-887","article-title":"The \u2018Arctic\u2019 APP mutation (E693G) causes Alzheimer\u2019s disease by enhanced Abeta protofibril formation","volume":"4","author":"Nilsberth","year":"2001","journal-title":"Nat Neurosci"}],"container-title":["Journal of Alzheimer's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JAD-220194","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:06:06Z","timestamp":1777370766000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JAD-220194"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,14]]},"references-count":26,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.3233\/jad-220194","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,14]]}}}