{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T06:48:10Z","timestamp":1791010090193,"version":"4.1.0"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2012,8,20]],"date-time":"2012-08-20T00:00:00Z","timestamp":1345420800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2012,8,20]],"date-time":"2012-08-20T00:00:00Z","timestamp":1345420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Alz Res Therapy"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Some familial Alzheimer's disease (AD) cases are caused by rare and highly-penetrant mutations in\n                      <jats:italic>APP<\/jats:italic>\n                      ,\n                      <jats:italic>PSEN1<\/jats:italic>\n                      , and\n                      <jats:italic>PSEN2<\/jats:italic>\n                      . Mutations in\n                      <jats:italic>GRN<\/jats:italic>\n                      and\n                      <jats:italic>MAPT<\/jats:italic>\n                      , two genes associated with frontotemporal dementia (FTD), have been found in clinically diagnosed AD cases. Due to the dramatic developments in next-generation sequencing (NGS), high-throughput sequencing of targeted genomic regions of the human genome in many individuals in a single run is now cheap and feasible. Recent findings favor the\n                      <jats:italic>rare variant-common disease<\/jats:italic>\n                      hypothesis by which the combination effects of rare variants could explain a large proportion of the heritability. We utilized NGS to identify rare and pathogenic variants in\n                      <jats:italic>APP<\/jats:italic>\n                      ,\n                      <jats:italic>PSEN1<\/jats:italic>\n                      ,\n                      <jats:italic>PSEN2<\/jats:italic>\n                      ,\n                      <jats:italic>GRN<\/jats:italic>\n                      , and\n                      <jats:italic>MAPT<\/jats:italic>\n                      in an Ibero-American cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed pooled-DNA sequencing of each exon and flanking sequences in\n                      <jats:italic>APP, PSEN1, PSEN2, MAPT<\/jats:italic>\n                      and\n                      <jats:italic>GRN<\/jats:italic>\n                      in 167 clinical and 5 autopsy-confirmed AD cases (15 familial early-onset, 136 sporadic early-onset and 16 familial late-onset) from Spain and Uruguay using NGS. Follow-up genotyping was used to validate variants. After genotyping additional controls, we performed segregation and functional analyses to determine the pathogenicity of validated variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a novel G to T transition (g.38816G&gt;T) in exon 6 of\n                      <jats:italic>PSEN1<\/jats:italic>\n                      in a sporadic early-onset AD case, resulting in a previously described pathogenic p.L173F mutation. A pathogenic p.L392V mutation in exon 11 was found in one familial early-onset AD case. We also identified a novel CC insertion (g.10974_10975insCC) in exon 8 of\n                      <jats:italic>GRN<\/jats:italic>\n                      , which introduced a premature stop codon, resulting in nonsense-mediated mRNA decay. This\n                      <jats:italic>GRN<\/jats:italic>\n                      mutation was associated with lower GRN plasma levels, as previously reported for other\n                      <jats:italic>GRN<\/jats:italic>\n                      pathogenic mutations. We found two variants in\n                      <jats:italic>MAPT<\/jats:italic>\n                      (p.A152T, p.S318L) present only in three AD cases but not controls, suggesting that these variants could be risk factors for the disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We found pathogenic mutations in\n                      <jats:italic>PSEN1<\/jats:italic>\n                      ,\n                      <jats:italic>GRN<\/jats:italic>\n                      and\n                      <jats:italic>MAPT<\/jats:italic>\n                      in 2.33% of the screened cases. This study suggests that pathogenic mutations or risk variants in\n                      <jats:italic>MAPT<\/jats:italic>\n                      and in\n                      <jats:italic>GRN<\/jats:italic>\n                      are as frequent in clinical AD cases as mutations in\n                      <jats:italic>APP<\/jats:italic>\n                      ,\n                      <jats:italic>PSEN1<\/jats:italic>\n                      and\n                      <jats:italic>PSEN2<\/jats:italic>\n                      , highlighting that pleiotropy of\n                      <jats:italic>MAPT<\/jats:italic>\n                      or\n                      <jats:italic>GRN<\/jats:italic>\n                      mutations can influence both FTD and AD phenotypic traits.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/alzrt137","type":"journal-article","created":{"date-parts":[[2012,8,21]],"date-time":"2012-08-21T09:46:02Z","timestamp":1345542362000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort"],"prefix":"10.1186","volume":"4","author":[{"given":"Sheng Chih","family":"Jin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pau","family":"Pastor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Breanna","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Cervantes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno A","family":"Benitez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Razquin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Goate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Ibero-American Alzheimer Disease Genetics Group Researchers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,8,20]]},"reference":[{"key":"117_CR1","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1001\/archneur.60.8.1119","volume":"60","author":"LE Hebert","year":"2003","unstructured":"Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA: Alzheimer disease in the US population: prevalence estimates using the 2000 census. 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