{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T21:53:03Z","timestamp":1788472383249,"version":"build-2803163510"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T00:00:00Z","timestamp":1705363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Royalty Research Fund of the University of Washington","award":["A167463"],"award-info":[{"award-number":["A167463"]}]},{"name":"US Department of Veterans Affairs Clinical Sciences R&D Service Merit Review","award":["101 CX001702"],"award-info":[{"award-number":["101 CX001702"]}]},{"name":"The Takayama family gift"},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01NS122766"],"award-info":[{"award-number":["R01NS122766"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Loss-of-function variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are responsible for a spectrum of neurodegenerative disorders. In the homozygous state, they cause severe pathologies with early onset dementia, such as Nasu-Hakola disease and behavioural variants of frontotemporal dementia (FTD), whereas heterozygous variants increase the risk of late-onset Alzheimer\u2019s disease (AD) and FTD. For over half of TREM2 variants found in families with recessive early onset dementia, the defect occurs at the transcript level via premature termination codons or aberrant splicing. The remaining variants are missense alterations thought to affect the protein; however, the underlying pathogenic mechanism is less clear. In this work, we tested whether these disease-associated TREM2 variants contribute to the pathology via altered splicing.<\/jats:p>\n                  <jats:p>Variants scored by SpliceAI algorithm were tested by a full-size TREM2 splicing reporter assay in different cell lines. The effect of variants was quantified by qRT-\/RT-PCR and western blots. Nanostring nCounter was used to measure TREM2 RNA in the brains of NHD patients who carried spliceogenic variants. Exon skipping events were analysed from brain RNA-Seq datasets available through the Accelerating Medicines Partnership for Alzheimer\u2019s Disease Consortium.<\/jats:p>\n                  <jats:p>We found that for some Nasu-Hakola disease and early onset FTD-causing variants, splicing defects were the primary cause (D134G) or likely contributor to pathogenicity (V126G and K186N). Similar but milder effects on splicing of exons 2 and 3 were demonstrated for A130V, L133L and R136W enriched in patients with dementia. Moreover, the two most frequent missense variants associated with AD\/FTD risk in European and African ancestries (R62H, 1% in Caucasians and T96K, 12% in Africans) had splicing defects via excessive skipping of exon 2 and overproduction of a potentially antagonistic TREM2 protein isoform. The effect of R62H on exon 2 skipping was confirmed in three independent brain RNA-Seq datasets.<\/jats:p>\n                  <jats:p>Our findings revealed an unanticipated complexity of pathogenic variation in TREM2, in which effects on post-transcriptional gene regulation and protein function often coexist. This necessitates the inclusion of computational and experimental analyses of splicing and mRNA processing for a better understanding of genetic variation in disease.<\/jats:p>","DOI":"10.1093\/brain\/awae014","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T07:27:36Z","timestamp":1705390056000},"page":"2368-2383","source":"Crossref","is-referenced-by-count":19,"title":["<i>TREM2<\/i>\n                    variants that cause early dementia and increase Alzheimer\u2019s disease risk affect gene splicing"],"prefix":"10.1093","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9572-3591","authenticated-orcid":false,"given":"Kostantin","family":"Kiianitsa","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E","family":"Lukes","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J","family":"Hayes","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianna N","family":"Brutman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8840-6969","authenticated-orcid":false,"given":"Paul N","family":"Valdmanis","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D","family":"Bird","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Washington , Seattle, WA 98195 , USA"},{"name":"Geriatric Research, Education and Clinical Center (GRECC), VA Puget Sound Medical Center , Seattle, WA 98108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy H","family":"Raskind","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington , Seattle, WA 98195 , USA"},{"name":"Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Medical Center , Seattle, WA 98108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0070-000X","authenticated-orcid":false,"given":"Olena","family":"Korvatska","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"2024070507231725200_awae014-B1","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.4049\/jimmunol.177.4.2051","article-title":"Cutting edge: Inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12","volume":"177","author":"Hamerman","year":"2006","journal-title":"J Immunol"},{"key":"2024070507231725200_awae014-B2","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1007\/s00109-007-0191-4","article-title":"Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response","volume":"85","author":"Kiialainen","year":"2007","journal-title":"J Mol Med 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