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Based on this and other observations we hypothesized that familial Alzheimer's disease (FAD) mutations in PS2 would have a dramatic effect on function in order to have an observable effect on A\u03b2 levels in the presence of normal PS1 alleles. Only four of the eight reported FAD mutations in PS2 have altered function <jats:italic>in vitro<\/jats:italic> suggesting that the other variants represent rare polymorphisms rather than disease\u2010causing mutations. In support of our hypothesis, the four verified PS2 FAD mutations cause substantial changes in the A\u03b2 42\/40 ratio, comparable with PS1 mutations that cause very\u2010early\u2010onset FAD. Most of the PS2 mutations also cause a significant decrease in A\u03b2 40, APP C\u2010terminal fragment (CTF)\u03b3 and Notch intracellular domain (NICD) production suggesting that they are partial loss of function mutations. PS2 M239V, its PS1 homolog M233V, and other FAD mutations within transmembrane (TM)\u20035 of PS1 differentially affect CTF\u03b3 and NICD production suggesting that TM5 of PS are important for \u03b3\u2010secretase cleavage of APP but not Notch.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2004.02858.x","type":"journal-article","created":{"date-parts":[[2005,1,10]],"date-time":"2005-01-10T09:15:26Z","timestamp":1105348526000},"page":"294-301","source":"Crossref","is-referenced-by-count":146,"title":["Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in A\u03b2 42\/40 ratios"],"prefix":"10.1111","volume":"92","author":[{"given":"Emily S.","family":"Walker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maribel","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne L.","family":"Brunkan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Goate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,12,9]]},"reference":[{"key":"e_1_2_19_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(199911)14:5<433::AID-HUMU10>3.0.CO;2-K"},{"key":"e_1_2_19_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80230-5"},{"key":"e_1_2_19_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1058783"},{"key":"e_1_2_19_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205093200"},{"key":"e_1_2_19_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.1.43"},{"key":"e_1_2_19_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(99)00033-7"},{"key":"e_1_2_19_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.16.1665"},{"key":"e_1_2_19_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/34910"},{"key":"e_1_2_19_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/19083"},{"key":"e_1_2_19_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/383710a0"},{"key":"e_1_2_19_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb960"},{"key":"e_1_2_19_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/349704a0"},{"key":"e_1_2_19_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.04.018"},{"key":"e_1_2_19_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.21.11872"},{"key":"e_1_2_19_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/35017105"},{"key":"e_1_2_19_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C100447200"},{"key":"e_1_2_19_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.4.1683"},{"key":"e_1_2_19_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0296-224"},{"key":"e_1_2_19_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300974200"},{"key":"e_1_2_19_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s100480050044"},{"key":"e_1_2_19_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7638622"},{"key":"e_1_2_19_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80231-7"},{"key":"e_1_2_19_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.12.7109"},{"key":"e_1_2_19_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(200009)48:3<376::AID-ANA13>3.0.CO;2-U"},{"key":"e_1_2_19_26_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.57.10.1926"},{"key":"e_1_2_19_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.33.20655"},{"key":"e_1_2_19_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03401825"},{"key":"e_1_2_19_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.112686799"},{"key":"e_1_2_19_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.1.215"},{"key":"e_1_2_19_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.6.3263"},{"key":"e_1_2_19_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/376775a0"},{"key":"e_1_2_19_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80244-5"},{"key":"e_1_2_19_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/375754a0"},{"key":"e_1_2_19_35_1","first-page":"S312","article-title":"Novel presenilin 1 and presenilin 2 mutations in early\u2010onset Alzheimer's disease families","volume":"23","author":"Sorbi S.","year":"2002","journal-title":"Neurobiol. 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