{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:11:03Z","timestamp":1791288663538,"version":"4.3.0"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2010,10,28]],"date-time":"2010-10-28T00:00:00Z","timestamp":1288224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2010,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective:<\/jats:title><jats:p>Frontotemporal lobar degeneration (FTLD) is the most common cause of early\u2010onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans\u2010activating response element (TAR) DNA binding protein (TDP\u201043) and\/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD\u2010MND pedigree with no mutations in known dementia genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>We identified a nonpolymorphic mutation (c.672*51G&gt;T) in the 3\u2032\u2010untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (<jats:italic>SIGMAR1<\/jats:italic>) gene in affected individuals from the FTLD\u2010MND pedigree. The c.672*51G&gt;T mutation increased gene expression by 1.4\u2010fold, corresponding with a significant 1.5\u2010fold to 2\u2010fold change in the <jats:italic>SIGMAR1<\/jats:italic> transcript or Sigma\u20101 protein in lymphocyte or brain tissue. Brains of <jats:italic>SIGMAR1<\/jats:italic> mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP\u201043 or FUS but not Sigma\u20101. Overexpression of <jats:italic>SIGMAR1<\/jats:italic> shunted TDP\u201043 and FUS from the nucleus to the cytoplasm by 2.3\u2010fold and 5.2\u2010fold, respectively. Treatment of cells with Sigma\u20101 ligands significantly altered translocation of TDP\u201043 by up to 2\u2010fold.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation:<\/jats:title><jats:p><jats:italic>SIGMAR1<\/jats:italic> is a causative gene for familial FTLD\u2010MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma\u20101 drugs as potential treatments for the TDP\u201043\/FUS proteinopathies. Ann Neurol 2010;68:639\u2013649<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.22274","type":"journal-article","created":{"date-parts":[[2010,10,29]],"date-time":"2010-10-29T12:16:14Z","timestamp":1288354574000},"page":"639-649","source":"Crossref","is-referenced-by-count":180,"title":["Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration\u2013motor neuron disease"],"prefix":"10.1002","volume":"68","author":[{"given":"Agnes A.","family":"Luty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.J.","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Dobson\u2010Stone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clement T.","family":"Loy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten 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