{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:28:57Z","timestamp":1791210537506,"version":"4.1.0"},"reference-count":24,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,6,9]]},"abstract":"<jats:p>\n                    Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and myotubes. To determine whether loss-of-function mutations in\n                    <jats:italic>TBC1D4<\/jats:italic>\n                    might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulin-resistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in\n                    <jats:italic>TBC1D4<\/jats:italic>\n                    . After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, we further characterized the biological effects of the truncated protein in 3T3L1 adipocytes. Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.053) and significantly reduced insulin-stimulated GLUT4 cell membrane translocation (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05). When coexpressed with wild-type TBC1D4, the truncated protein dimerized with full-length TBC1D4, suggesting that the heterozygous truncated variant might interfere with its wild-type counterpart in a dominant negative fashion. Two overweight family members with the mutation also manifested normal fasting glucose and insulin levels but disproportionately elevated insulin levels following an oral glucose challenge. This family provides unique genetic evidence of TBC1D4 involvement in human insulin action.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0900909106","type":"journal-article","created":{"date-parts":[[2009,5,22]],"date-time":"2009-05-22T21:46:27Z","timestamp":1243028787000},"page":"9350-9355","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":97,"title":["A truncation mutation in\n                    <i>TBC1D4<\/i>\n                    in a family with acanthosis nigricans and postprandial hyperinsulinemia"],"prefix":"10.1073","volume":"106","author":[{"given":"Satya","family":"Dash","sequence":"first","affiliation":[{"name":"Departments of Medicine and Clinical Biochemistry, University of Cambridge, Box 289 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Sano","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, NH 03755-3844;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin J.","family":"Rochford","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Clinical Biochemistry, University of Cambridge, Box 289 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Semple","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Clinical Biochemistry, University of Cambridge, Box 289 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giles","family":"Yeo","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Clinical Biochemistry, University of Cambridge, Box 289 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline S. S.","family":"Hyden","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Clinical Biochemistry, University of Cambridge, Box 289 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Soos","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Clinical Biochemistry, University of Cambridge, Box 289 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, St. Helier's Hospital, Wrythe Lane, Carshalton, Surrey SM5 1AA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Rodin","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, St. Helier's Hospital, Wrythe Lane, Carshalton, Surrey SM5 1AA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Langenberg","sequence":"additional","affiliation":[{"name":"Medical Research Council Epidemiology Unit, University of Cambridge, Box 289 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Druet","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (C.D.), U690, FR-75019 Paris, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Fawcett","sequence":"additional","affiliation":[{"name":"The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. C. Loraine","family":"Tung","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Clinical Biochemistry, University of Cambridge, Box 289 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas J.","family":"Wareham","sequence":"additional","affiliation":[{"name":"Medical Research Council Epidemiology Unit, University of Cambridge, Box 289 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas","family":"Barroso","sequence":"additional","affiliation":[{"name":"The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustav E.","family":"Lienhard","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, 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