{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:10:35Z","timestamp":1790730635095,"version":"4.1.0"},"reference-count":21,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2017,5,25]],"date-time":"2017-05-25T00:00:00Z","timestamp":1495670400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2017,6,23]]},"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    The presenilin-1 protein (PS1) is the catalytic unit of\n                    <jats:italic>\u03b3<\/jats:italic>\n                    -secretase implicated in the production of abnormally long forms of amyloid-\u03b2 (A\u03b2), including A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    , proteins thought critical in the pathogenesis of Alzheimer\u2019s disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the\n                    <jats:italic>PSEN1<\/jats:italic>\n                    gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Objective:<\/jats:bold>\n                    To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of\n                    <jats:italic>PSEN1<\/jats:italic>\n                    as well as biochemical features in one and neuropathological findings in the other.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as\n                    <jats:italic>PSEN1<\/jats:italic>\n                    sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on\n                    <jats:italic>\u03b3<\/jats:italic>\n                    -secretase cleavage.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    and decreased APP and Notch intracellular domain production\n                    <jats:italic>in vitro<\/jats:italic>\n                    .\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the\n                    <jats:italic>\u03b3<\/jats:italic>\n                    -secretase cleavage of A\u03b2.\n                  <\/jats:p>","DOI":"10.3233\/jad-161203","type":"journal-article","created":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T14:46:28Z","timestamp":1495809988000},"page":"1035-1041","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":24,"title":["Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"58","author":[{"given":"Collin Y.","family":"Liu","sequence":"first","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Ohki","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taisuke","family":"Tomita","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Osawa","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce R.","family":"Reed","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, UC Davis, Davis, CA, USA"},{"name":"Center for Scientific Review, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Jagust","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, UC Davis, Davis, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Van Berlo","sequence":"additional","affiliation":[{"name":"Semel Institute at UCLA, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee-Way","family":"Jin","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, UC Davis, Davis, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena C.","family":"Chui","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Coppola","sequence":"additional","affiliation":[{"name":"Semel Institute at UCLA, Los Angeles, CA, USA"},{"name":"Easton Center for Alzheimer\u2019s Disease Research, UCLA, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Ringman","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA"},{"name":"Easton Center for Alzheimer\u2019s Disease Research, UCLA, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2017,5,25]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-9-7"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.629287"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00012.x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1039\/b306970b"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200148200"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv112"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0910-3"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2006-9S347"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.79"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.112686799"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.28.7.1418"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2008.06.012"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-012-6481-y"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)30229-0"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)30193-4"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.2217\/bmm.09.92"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/120.3.491"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.72.2.266"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.530907"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvu049"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1402171111"}],"container-title":["Journal 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