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TBC1D4
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<h2 id="isoforms">Isoforms</h2> <p>The <i>TBC1D4</i> gene has two <a href="/facts/Protein_isoform/oWmzfg4l">isoforms</a> - a long isoform expressed almost exclusively in skeletal and cardiac muscle, and a short isoform with more widespread expression.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h2 id="pathogenic-mutations">Pathogenic mutations</h2> <p>A nonsense p.Arg684Ter variant in the <i>TBC1D4</i> gene has been identified in the <a href="/facts/Greenlandic_Inuit/fmt7WPD4">Greenlandic Inuit</a> population that is associated with increased risk of <a href="/facts/Type_2_diabetes/zCMXksmt">type II diabetes</a>. The variant mainly affects individuals with two copies of the mutation, indicating <a href="/facts/Recessive_inheritance/zAVE0adY">recessive inheritance</a>. Although the mutation does not effect the short isoform of the protein, it introduces a premature stop codon in the long isoform, resulting in the absence of the long isoform protein in muscle tissue.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p><a href="/facts/Homozygous/XzEJ5gPp">Homozygous</a> carriers of the p.Arg684Ter allele have lower concentrations of fasting plasma glucose and insulin. They also have a markedly increased risk of <a href="/facts/Type_2_diabetes/zCMXksmt">Type II Diabetes</a> — individuals with two mutant genes have about 10 times the chance of contracting Type II diabetes (<a href="/facts/Odds_ratio/7WcmubfN">odds ratio</a> = 10.3) compared to noncarriers. Approximately 3.8% of Greenlanders are homozygous for the mutation, which is estimated to be responsible for approximately 10% of Type II Diabetes cases in Greenland.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Chen S, Wasserman DH, MacKintosh C, Sakamoto K (January 2011). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081066">"Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking"</a>. <i>Cell Metabolism</i>. 13 (1): 68–79. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.cmet.2010.12.005">10.1016/j.cmet.2010.12.005</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081066">3081066</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/21195350">21195350</a>.</li> <li>Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, et al. (February 1998). <a href="https://doi.org/10.1093%2Fdnares%2F5.1.31">"Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro"</a>. <i>DNA Research</i>. 5 (1): 31–39. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Fdnares%2F5.1.31">10.1093/dnares/5.1.31</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9628581">9628581</a>.</li> <li>Nakayama M, Kikuno R, Ohara O (November 2002). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC187542">"Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs"</a>. <i>Genome Research</i>. 12 (11): 1773–1784. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1101%2Fgr.406902">10.1101/gr.406902</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC187542">187542</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12421765">12421765</a>.</li> <li>Lee SY, Obata Y, Yoshida M, Stockert E, Williamson B, Jungbluth AA, et al. (March 2003). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC151395">"Immunomic analysis of human sarcoma"</a>. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 100 (5): 2651–2656. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2003PNAS..100.2651L">2003PNAS..100.2651L</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1073%2Fpnas.0437972100">10.1073/pnas.0437972100</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC151395">151395</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12601173">12601173</a>.</li> <li>Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, et al. (August 2004). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC514446">"Large-scale characterization of HeLa cell nuclear phosphoproteins"</a>. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 101 (33): 12130–12135. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2004PNAS..10112130B">2004PNAS..10112130B</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1073%2Fpnas.0404720101">10.1073/pnas.0404720101</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC514446">514446</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15302935">15302935</a>.</li> <li>Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, et al. (August 2004). <a href="https://doi.org/10.1016%2Fj.cub.2004.07.051">"Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization"</a>. <i>Current Biology</i>. 14 (16): 1436–1450. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2004CBio...14.1436J">2004CBio...14.1436J</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.cub.2004.07.051">10.1016/j.cub.2004.07.051</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15324660">15324660</a>.</li> <li>Karlsson HK, Zierath JR, Kane S, Krook A, Lienhard GE, Wallberg-Henriksson H (June 2005). <a href="https://doi.org/10.2337%2Fdiabetes.54.6.1692">"Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects"</a>. <i>Diabetes</i>. 54 (6): 1692–1697. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.2337%2Fdiabetes.54.6.1692">10.2337/diabetes.54.6.1692</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15919790">15919790</a>.</li> <li>Kim JE, Tannenbaum SR, White FM (2005). "Global phosphoproteome of HT-29 human colon adenocarcinoma cells". <i>Journal of Proteome Research</i>. 4 (4): 1339–1346. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1021%2Fpr050048h">10.1021/pr050048h</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16083285">16083285</a>.</li> <li>Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (October 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". <i>Nature Biotechnology</i>. 24 (10): 1285–1292. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fnbt1240">10.1038/nbt1240</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16964243">16964243</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:14294292">14294292</a>.</li> <li>Treebak JT, Birk JB, Rose AJ, Kiens B, Richter EA, Wojtaszewski JF (March 2007). "AS160 phosphorylation is associated with activation of alpha2beta2gamma1- but not alpha2beta2gamma3-AMPK trimeric complex in skeletal muscle during exercise in humans". <i>American Journal of Physiology. Endocrinology and Metabolism</i>. 292 (3): E715 – E722. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1152%2Fajpendo.00380.2006">10.1152/ajpendo.00380.2006</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17077344">17077344</a>.</li> <li>Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. (November 2006). <a href="https://doi.org/10.1016%2Fj.cell.2006.09.026">"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks"</a>. <i>Cell</i>. 127 (3): 635–648. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.cell.2006.09.026">10.1016/j.cell.2006.09.026</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17081983">17081983</a>.</li> <li>Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847948">"Large-scale mapping of human protein-protein interactions by mass spectrometry"</a>. <i>Molecular Systems Biology</i>. 3 (1): 89. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fmsb4100134">10.1038/msb4100134</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847948">1847948</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17353931">17353931</a>.</li> <li>Howlett KF, Sakamoto K, Garnham A, Cameron-Smith D, Hargreaves M (June 2007). <a href="https://doi.org/10.2337%2Fdb06-1398">"Resistance exercise and insulin regulate AS160 and interaction with 14-3-3 in human skeletal muscle"</a>. <i>Diabetes</i>. 56 (6): 1608–1614. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.2337%2Fdb06-1398">10.2337/db06-1398</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17369524">17369524</a>.</li> <li>Frøsig C, Rose AJ, Treebak JT, Kiens B, Richter EA, Wojtaszewski JF (August 2007). <a href="https://doi.org/10.2337%2Fdb06-1698">"Effects of endurance exercise training on insulin signaling in human skeletal muscle: interactions at the level of phosphatidylinositol 3-kinase, Akt, and AS160"</a>. <i>Diabetes</i>. 56 (8): 2093–2102. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.2337%2Fdb06-1698">10.2337/db06-1698</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17513702">17513702</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Sakamoto K, Holman GD (July 2008). "Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic". American Journal of Physiology. Endocrinology and Metabolism. 295 (1): E29 – E37. doi:10.1152/ajpendo.90331.2008. PMC 2493596. PMID 18477703. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493596" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493596</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Kurihara LJ, Semenova E, Miller W, Ingram RS, Guan XJ, Tilghman SM (February 2002). "Candidate genes required for embryonic development: a comparative analysis of distal mouse chromosome 14 and human chromosome 13q22". Genomics. 79 (2): 154–161. CiteSeerX 10.1.1.16.1099. doi:10.1006/geno.2002.6692. PMID 11829485. <a href="/wiki/CiteSeerX_(identifier)" target="_blank">/wiki/CiteSeerX_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, et al. (June 2002). "A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain". The Journal of Biological Chemistry. 277 (25): 22115–22118. doi:10.1074/jbc.C200198200. PMID 11994271. <a href="https://doi.org/10.1074%2Fjbc.C200198200" target="_blank">https://doi.org/10.1074%2Fjbc.C200198200</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Matsumoto Y, Imai Y, Lu Yoshida N, Sugita Y, Tanaka T, Tsujimoto G, et al. (August 2004). "Upregulation of the transcript level of GTPase activating protein KIAA0603 in T cells from patients with atopic dermatitis". FEBS Letters. 572 (1–3): 135–140. Bibcode:2004FEBSL.572..135M. doi:10.1016/j.febslet.2004.07.023. PMID 15304337. <a href="https://doi.org/10.1016%2Fj.febslet.2004.07.023" target="_blank">https://doi.org/10.1016%2Fj.febslet.2004.07.023</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>"Entrez Gene: TBC1D4 TBC1 domain family, member 4". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9882" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9882</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Sakamoto K, Holman GD (July 2008). "Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic". American Journal of Physiology. Endocrinology and Metabolism. 295 (1): E29 – E37. doi:10.1152/ajpendo.90331.2008. PMC 2493596. PMID 18477703. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493596" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493596</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Sano H, Kane S, Sano E, Mîinea CP, Asara JM, Lane WS, et al. (April 2003). "Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation". The Journal of Biological Chemistry. 278 (17): 14599–14602. doi:10.1074/jbc.C300063200. PMID 12637568. <a href="https://doi.org/10.1074%2Fjbc.C300063200" target="_blank">https://doi.org/10.1074%2Fjbc.C300063200</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, et al. (June 2002). "A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain". The Journal of Biological Chemistry. 277 (25): 22115–22118. doi:10.1074/jbc.C200198200. PMID 11994271. <a href="https://doi.org/10.1074%2Fjbc.C200198200" target="_blank">https://doi.org/10.1074%2Fjbc.C200198200</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Sano H, Kane S, Sano E, Mîinea CP, Asara JM, Lane WS, et al. (April 2003). "Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation". The Journal of Biological Chemistry. 278 (17): 14599–14602. doi:10.1074/jbc.C300063200. PMID 12637568. <a href="https://doi.org/10.1074%2Fjbc.C300063200" target="_blank">https://doi.org/10.1074%2Fjbc.C300063200</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Mîinea CP, Sano H, Kane S, Sano E, Fukuda M, Peränen J, et al. (October 2005). "AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain". The Biochemical Journal. 391 (Pt 1): 87–93. doi:10.1042/BJ20050887. PMC 1237142. PMID 15971998. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1237142" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1237142</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Kramer HF, Taylor EB, Witczak CA, Fujii N, Hirshman MF, Goodyear LJ (December 2007). "Calmodulin-binding domain of AS160 regulates contraction- but not insulin-stimulated glucose uptake in skeletal muscle". Diabetes. 56 (12): 2854–2862. doi:10.2337/db07-0681. PMID 17717281. <a href="https://doi.org/10.2337%2Fdb07-0681" target="_blank">https://doi.org/10.2337%2Fdb07-0681</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Moltke I, Grarup N, Jørgensen ME, Bjerregaard P, Treebak JT, Fumagalli M, et al. (August 2014). "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes". Nature. 512 (7513): 190–193. Bibcode:2014Natur.512..190M. doi:10.1038/nature13425. PMID 25043022. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Moltke I, Grarup N, Jørgensen ME, Bjerregaard P, Treebak JT, Fumagalli M, et al. (August 2014). "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes". Nature. 512 (7513): 190–193. Bibcode:2014Natur.512..190M. doi:10.1038/nature13425. PMID 25043022. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Moltke I, Grarup N, Jørgensen ME, Bjerregaard P, Treebak JT, Fumagalli M, et al. (August 2014). "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes". Nature. 512 (7513): 190–193. Bibcode:2014Natur.512..190M. doi:10.1038/nature13425. PMID 25043022. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> </ol>