{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:17:50Z","timestamp":1791555470526,"version":"4.3.4"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,10,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunoglobulin-like receptor expressed by certain myeloid cells, such as macrophages, dendritic cells, osteoclasts, and microglia. In the brain, TREM2 plays an important role in the immune function of microglia, and its dysfunction is linked to various neurodegenerative conditions in humans. Ablation of TREM2 or its adaptor protein TYROBP causes polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (also known as Nasu-Hakola disorder) with early onset of dementia, whereas some missense variants in TREM2 are associated with an increased risk of late-onset Alzheimer's disease. The human TREM2 gene is subject to alternative splicing, and its major, full-length canonic transcript encompasses 5 exons. Herein, we report a novel alternatively spliced TREM2 isoform without exon 2 (\u0394e2), which constitutes a sizable fraction of TREM2 transcripts and has highly variable inter-individual expression in the human brain (average frequency 10%; range 3.7\u201335%). The protein encoded by \u0394e2 lacks a V-set immunoglobulin domain from its extracellular part but retains its transmembrane and cytoplasmic domains. We demonstrated \u0394e2 protein expression in TREM2-positive THP-1 cells, in which the expression of full-length transcript was precluded by CRISPR\/Cas9 disruption of the exon 2 coding frame. Similar to the full-length TREM2, \u0394e2 is sorted to the plasma membrane and is subject to receptor shedding. In \u201cadd-back\u201d experiments, \u0394e2 TREM2 had diminished capacity to restore phagocytosis of amyloid beta peptide and promote IFN-I response as compared to full-length TREM2. Our findings suggest that changes in the balance of two mutually exclusive TREM2 isoforms may modify the dosage of full-length transcript potentially weakening some TREM2 receptor functions in the human brain.<\/jats:p>","DOI":"10.1002\/jlb.2hi0720-463rr","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T21:01:02Z","timestamp":1622581262000},"page":"829-837","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Novel TREM2 splicing isoform that lacks the V-set immunoglobulin domain is abundant in the human brain"],"prefix":"10.1093","volume":"110","author":[{"given":"Kostantin","family":"Kiianitsa","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Washington , Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Kurtz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington , Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal","family":"Beeman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington , Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington , Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ming","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington , Seattle, Washington, 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, Washington, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington , Seattle, Washington, USA"},{"name":"Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Medical Center , Seattle, Washington, USA"},{"name":"Geriatric Research, Education and Clinical Center (GRECC), VA Puget Sound Medical Center , Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olena","family":"Korvatska","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington , Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"key":"2023032108463385100_","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/s41582-018-0072-1","article-title":"TREM2\u2014a key player in microglial biology and Alzheimer disease","volume":"14","author":"Ulland","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"2023032108463385100_","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1086\/342259","article-title":"Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype","volume":"71","author":"Paloneva","year":"2002","journal-title":"Am J Hum Genet"},{"key":"2023032108463385100_","doi-asserted-by":"crossref","DOI":"10.1016\/j.neurobiolaging.2013.06.005","article-title":"Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family","volume":"34","author":"Guerreiro","year":"2013","journal-title":"Neurobiol Aging"},{"key":"2023032108463385100_","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1001\/jamaneurol.2013.579","article-title":"Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement","volume":"70","author":"Guerreiro","year":"2013","journal-title":"JAMA Neurol"},{"key":"2023032108463385100_","doi-asserted-by":"crossref","DOI":"10.1016\/j.neurobiolaging.2014.04.010","article-title":"Homozygous TREM2 mutation in a family with atypical frontotemporal dementia","volume":"35","author":"Le Ber","year":"2014","journal-title":"Neurobiol Aging"},{"key":"2023032108463385100_","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1056\/NEJMoa1211851","article-title":"TREM2 variants in Alzheimer's disease","volume":"368","author":"Guerreiro","year":"2012","journal-title":"N Engl J Med"},{"key":"2023032108463385100_","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1056\/NEJMoa1211103","article-title":"Variant of TREM2 associated with the risk of Alzheimer's disease","volume":"368","author":"Jonsson","year":"2012","journal-title":"N Engl J 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Neurodegener"},{"key":"2023032108463385100_","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1001\/jamaneurol.2013.6237","article-title":"TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis","volume":"71","author":"Cady","year":"2014","journal-title":"JAMA Neurol"},{"key":"2023032108463385100_","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.cell.2020.05.003","article-title":"The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway","volume":"181","author":"Deczkowska","year":"2020","journal-title":"Cell"},{"key":"2023032108463385100_","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3009093","article-title":"TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis","volume":"6","author":"Kleinberger","year":"2014","journal-title":"Sci Transl 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