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2073-44258102017Oct02GenesGenes (Basel)Dystrophin Dp116: A yet to Be Investigated Product of the Duchenne Muscular Dystrophy Gene.25110.3390/genes8100251The Duchenne muscular dystrophy (DMD) gene is one of the largest genes in the human genome. The gene exhibits a complex arrangement of seven alternative promoters, which drive the expression of three full length and four shorter isoforms. Dp116, the second smallest product of the DMD gene, is a Schwann cell-specific isoform encoded by a transcript corresponding to DMD exons 56-79, starting from a promoter/exon S1 within intron 55. The physiological roles of Dp116 are poorly understood, because of its extensive homology with other isoforms and its expression in specific tissues. This review summarizes studies on Dp116, focusing on clinical findings and alternative activation of the upstream translation initiation codon that is predicted to produce Dp118.MatsuoMasafumiMDepartment of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University, Kobe 651-2180, Japan. mmatsuo@reha.kobegakuin.ac.jp.AwanoHiroyukiHDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. awahiro@med.kobe-u.ac.jp.MatsumotoMasaakiMDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. mmatsu@med.kobe-u.ac.jp.NagaiMasashiMDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. natsu@med.kobe-u.ac.jp.KawaguchiTatsuyaTBiomedical Analysis and Pathology Research Group, Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Tokyo 134-8630, Japan. kawaguchi.tatsuya.sg@rdn.daiichisankyo.co.jp.ZhangZhujunZDepartment of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University, Kobe 651-2180, Japan. zhang_zhujun@hotmail.com.NishioHisahideHDepartment of Community Medicine and Social Healthcare Sciences, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. nishio@lion.kobe-u.ac.jp.engJournal ArticleReview20171002
SwitzerlandGenes (Basel)1015510972073-4425Dp116Dp118Duchenne muscular dystrophySchwann celldystrophinisoformThe authors have no conflicts of interest relevant to this article to disclose.201781120179262017105602017105602017105612017101epublish28974057PMC566410110.3390/genes8100251genes8100251Bushby K., Finkel R., Birnkrant D.J., Case L.E., Clemens P.R., Cripe L., Kaul A., Kinnett K., McDonald C., Pandya S., et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9:77–93. doi: 10.1016/S1474-4422(09)70271-6.10.1016/S1474-4422(09)70271-619945913Emery A.E.H. Duchenne Muscular Dystrophy. 2nd ed. Volume 24. Oxford University Press; Oxford, UK: 1993. Confirmation of the diagnosis; pp. 45–79.Costa M.F., Oliveira A.G., Feitosa-Santana C., Zatz M., Ventura D.F. Red-green color vision impairment in Duchenne muscular dystrophy. Am. J. Hum. Genet. 2007;80:1064–1075. doi: 10.1086/518127.10.1086/518127PMC186709517503325Pillers D.A., Fitzgerald K.M., Duncan N.M., Rash S.M., White R.A., Dwinnell S.J., Powell B.R., Schnur R.E., Ray P.N., Cibis G.W., et al. Duchenne/Becker muscular dystrophy: Correlation of phenotype by electroretinography with sites of dystrophin mutations. Hum. Genet. 1999;105:2–9. doi: 10.1007/s004399900111.10.1007/s00439990011110480348Wood C.L., Straub V., Guglieri M., Bushby K., Cheetham T. Short stature and pubertal delay in Duchenne muscular dystrophy. Arch. Dis. Child. 2016;101:101–106. doi: 10.1136/archdischild-2015-308654.10.1136/archdischild-2015-30865426141541Matsumoto M., Awano H., Lee T., Takeshima Y., Matsuo M., Iijima K. Patients with Duchenne muscular dystrophy are significantly shorter than those with Becker muscular dystrophy, with the higher incidence of short stature in Dp71 mutated subgroup. Neuromuscul. Disord. 2017 doi: 10.1016/j.nmd.2017.06.007. in press.10.1016/j.nmd.2017.06.00728734761Muntoni F., Torelli S., Ferlini A. Dystrophin and mutations: One gene, several proteins, multiple phenotypes. Lancet Neurol. 2003;2:731–740. doi: 10.1016/S1474-4422(03)00585-4.10.1016/S1474-4422(03)00585-414636778Pillers D.A., Bulman D.E., Weleber R.G., Sigesmund D.A., Musarella M.A., Powell B.R., Murphey W.H., Westall C., Panton C., Becker L.E., et al. Dystrophin expression in the human retina is required for normal function as defined by electroretinography. Nat. Genet. 1993;4:82–86. doi: 10.1038/ng0593-82.10.1038/ng0593-828513332Ricotti V., Jagle H., Theodorou M., Moore A.T., Muntoni F., Thompson D.A. Ocular and neurodevelopmental features of Duchenne muscular dystrophy: A signature of dystrophin function in the central nervous system. Eur. J. Hum. Genet. 2016;24:562–568. doi: 10.1038/ejhg.2015.135.10.1038/ejhg.2015.135PMC492986326081639Doorenweerd N., Straathof C.S., Dumas E.M., Spitali P., Ginjaar I.B., Wokke B.H., Schrans D.G., van den Bergen J.C., van Zwet E.W., Webb A., et al. Reduced cerebral gray matter and altered white matter in boys with Duchenne muscular dystrophy. Ann. Neurol. 2014;76:403–411. doi: 10.1002/ana.24222.10.1002/ana.2422225043804Doorenweerd N., Dumas E.M., Ghariq E., Schmid S., Straathof C.S.M., Roest A.A.W., Wokke B.H., van Zwet E.W., Webb A.G., Hendriksen J.G.M., et al. Decreased cerebral perfusion in Duchenne muscular dystrophy patients. Neuromuscul. Disord. 2017;27:29–37. doi: 10.1016/j.nmd.2016.10.005.10.1016/j.nmd.2016.10.00527927595Tadayoni R., Rendon A., Soria-Jasso L.E., Cisneros B. Dystrophin Dp71: The smallest but multifunctional product of the Duchenne muscular dystrophy gene. Mol. Neurobiol. 2012;45:43–60. doi: 10.1007/s12035-011-8218-9.10.1007/s12035-011-8218-922105192Byers T.J., Lidov H.G., Kunkel L.M. An alternative dystrophin transcript specific to peripheral nerve. Nat. Genet. 1993;4:77–81. doi: 10.1038/ng0593-77.10.1038/ng0593-778513330Schofield J.N., Blake D.J., Simmons C., Morris G.E., Tinsley J.M., Davies K.E., Edwards Y.H. Apo-dystrophin-1 and apo-dystrophin-2, products of the Duchenne muscular dsytrophy locus: Expression during mouse embryogenesis and in cultured cell lines. Hum. Mol. Genet. 1994;3:1309–1316.7987307Mizuno Y., Yoshida M., Yamamoto H., Hirai S., Ozawa E. Distribution of dystrophin isoforms and dystrophin-associated proteins 43DAG (A3a) and 50DAG (A2) in various monkey tissues. J. Biochem. 1993;114:936–941. doi: 10.1093/oxfordjournals.jbchem.a124281.10.1093/oxfordjournals.jbchem.a12428181385551Blitzblau R., Storer E.K., Jacob M.H. Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion. Brain Res. 2008;1218:21–34. doi: 10.1016/j.brainres.2008.04.071.10.1016/j.brainres.2008.04.071PMC251225818533135Vita G., Mazzeo A., Muglia U., Girlanda P., Toscano A., Rodolico C., Migliorato A. Dp116, talin, vinculin and vimentin immunoreactivities following nerve transection. Neuroreport. 1998;9:697–702. doi: 10.1097/00001756-199803090-00025.10.1097/00001756-199803090-000259559941Matsumura K., Yamada H., Shimizu T., Campbell K.P. Differential expression of dystrophin, utrophin and dystrophin-associated proteins in peripheral nerve. FEBS Lett. 1993;334:281–285. doi: 10.1016/0014-5793(93)80695-Q.10.1016/0014-5793(93)80695-Q8243633Fabbrizio E., Latouche J., Rivier F., Hugon G., Mornet D. Re-evaluation of the distributions of dystrophin and utrophin in sciatic nerve. Biochem. J. 1995;312:309–314. doi: 10.1042/bj3120309.10.1042/bj3120309PMC11362607492329Cai H., Erdman R.A., Zweier L., Chen J., Shaw J.H., IV, Baylor K.A., Stecker M.M., Carey D.J., Chan Y.M. The sarcoglycan complex in Schwann cells and its role in myelin stability. Exp. Neurol. 2007;205:257–269. doi: 10.1016/j.expneurol.2007.02.015.10.1016/j.expneurol.2007.02.01517397833Imamura M., Araishi K., Noguchi S., Ozawa E. A sarcoglycan-dystroglycan complex anchors Dp116 and utrophin in the peripheral nervous system. Hum. Mol. Genet. 2000;9:3091–3100. doi: 10.1093/hmg/9.20.3091.10.1093/hmg/9.20.309111115854Hnia K., Hugon G., Masmoudi A., Mercier J., Rivier F., Mornet D. Effect of beta-dystroglycan processing on utrophin/Dp116 anchorage in normal and mdx mouse Schwann cell membrane. Neuroscience. 2006;141:607–620. doi: 10.1016/j.neuroscience.2006.04.043.10.1016/j.neuroscience.2006.04.043PMC1974842167350922Scherer S.S., Arroyo E.J. Recent progress on the molecular organization of myelinated axons. J. Peripher. Nerv. Syst. 2002;7:1–12. doi: 10.1046/j.1529-8027.2002.02001.x.10.1046/j.1529-8027.2002.02001.x11939347Sherman D.L., Wu L.M., Grove M., Gillespie C.S., Brophy P.J. Drp2 and periaxin form Cajal bands with dystroglycan but have distinct roles in Schwann cell growth. J. Neurosci. 2012;32:9419–9428. doi: 10.1523/JNEUROSCI.1220-12.2012.10.1523/JNEUROSCI.1220-12.2012PMC340094922764250Albrecht D.E., Sherman D.L., Brophy P.J., Froehner S.C. The ABCA1 cholesterol transporter associates with one of two distinct dystrophin-based scaffolds in Schwann cells. Glia. 2008;56:611–618. doi: 10.1002/glia.20636.10.1002/glia.20636PMC433517018286648Romo-Yanez J., Montanez C., Salazar-Olivo L.A. Dystrophins and DAPs are expressed in adipose tissue and are regulated by adipogenesis and extracellular matrix. Biochem. Biophys. Res. Commun. 2011;404:717–722. doi: 10.1016/j.bbrc.2010.12.049.10.1016/j.bbrc.2010.12.04921147070Taghli-Lamallem O., Akasaka T., Hogg G., Nudel U., Yaffe D., Chamberlain J.S., Ocorr K., Bodmer R. Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype. Aging Cell. 2008;7:237–249. doi: 10.1111/j.1474-9726.2008.00367.x.10.1111/j.1474-9726.2008.00367.xPMC284069818221418Guiraud S., Davies K.E. Pharmacological advances for treatment in Duchenne muscular dystrophy. Curr. Opin. Pharmacol. 2017;34:36–48. doi: 10.1016/j.coph.2017.04.002.10.1016/j.coph.2017.04.00228486179Blake D.J., Schofield J.N., Zuellig R.A., Gorecki D.C., Phelps S.R., Barnard E.A., Edwards Y.H., Davies K.E. G-utrophin, the autosomal homologue of dystrophin Dp116, is expressed in sensory ganglia and brain. Proc. Natl. Acad. Sci. USA. 1995;92:3697–3701. doi: 10.1073/pnas.92.9.3697.10.1073/pnas.92.9.3697PMC420287731967Knuesel I., Bornhauser B.C., Zuellig R.A., Heller F., Schaub M.C., Fritschy J.M. Differential expression of utrophin and dystrophin in CNS neurons: An in situ hybridization and immunohistochemical study. J. Comp. Neurol. 2000;422:594–611. doi: 10.1002/1096-9861(20000710)422:4<594::AID-CNE8>3.0.CO;2-Q.10.1002/1096-9861(20000710)422:4<594::AID-CNE8>3.0.CO;2-Q10861528Judge L.M., Arnett A.L., Banks G.B., Chamberlain J.S. Expression of the dystrophin isoform Dp116 preserves functional muscle mass and extends lifespan without preventing dystrophy in severely dystrophic mice. Hum. Mol. Genet. 2011;20:4978–4990. doi: 10.1093/hmg/ddr433.10.1093/hmg/ddr433PMC322153621949353Labarque V., Freson K., Thys C., Wittevrongel C., Hoylaerts M.F., De Vos R., Goemans N., Van Geet C. Increased Gs signalling in platelets and impaired collagen activation, due to a defect in the dystrophin gene, result in increased blood loss during spinal surgery. Hum. Mol. Genet. 2008;17:357–366. doi: 10.1093/hmg/ddm312.10.1093/hmg/ddm31217981813Sugimoto S., Tsuruta K., Kurihara T., Ono S., Morotomi Y., Inoue K., Matsukura S. Posterior tibial somatosensory evoked potentials in Duchenne-type progressive muscular dystrophy. Electroencephalogr. Clin. Neurophysiol. 1986;64:525–527. doi: 10.1016/0013-4694(86)90190-2.10.1016/0013-4694(86)90190-22430776Kraus D., Wong B.L., Horn P.S., Kaul A. Constipation in Duchenne muscular dystrophy: Prevalence, diagnosis, and treatment. J. Pediatr. 2016;171:183–188. doi: 10.1016/j.jpeds.2015.12.046.10.1016/j.jpeds.2015.12.04626831528Latimer R., Street N., Conway K.C., James K., Cunniff C., Oleszek J., Fox D., Ciafaloni E., Westfield C., Paramsothy P., et al. Secondary conditions among males with Duchenne or Becker muscular dystrophy. J. Child Neurol. 2017;32:663–670. doi: 10.1177/0883073817701368.10.1177/0883073817701368PMC550275628393671Lo Cascio C.M., Goetze O., Latshang T.D., Bluemel S., Frauenfelder T., Bloch K.E. Gastrointestinal dysfunction in patients with Duchenne muscular dystrophy. PLoS ONE. 2016;11:e0163779. doi: 10.1371/journal.pone.0163779.10.1371/journal.pone.0163779PMC506333227736891Hoffman E.P., Garcia C.A., Chamberlain J.S., Angelini C., Lupski J.R., Fenwick R. Is the carboxy-terminus of dystrophin required for membrane association? A novel, severe case of Duchenne muscular dystrophy. Ann. Neurol. 1991;30:605–610. doi: 10.1002/ana.410300414.10.1002/ana.4103004141789686Helliwell T.R., Ellis J.M., Mountford R.C., Appleton R.E., Morris G.E. A truncated dystrophin lacking the C-terminal domains is localized at the muscle membrane. Am. J. Hum. Genet. 1992;50:508–514.PMC16843021539591Recan D., Chafey P., Leturcq F., Hugnot J.P., Vincent N., Tome F., Collin H., Simon D., Czernichow P., Nichoson L.V.B., et al. Are cysteine-rich and COOH-terminal domains of dystrophin critical for sarcolemmal localization? J. Clin. Investig. 1992;89:712–716. doi: 10.1172/JCI115640.10.1172/JCI115640PMC4429071737859Wibawa T., Takeshima Y., Mitsuyoshi I., Wada H., Surono A., Nakamura H., Matsuo M. Complete skipping of exon 66 due to novel mutations of the dystrophin gene was identified in two Japanese families of Duchenne muscular dystrophy with severe mental retardation. Brain Dev. 2000;22:107–112. doi: 10.1016/S0387-7604(99)00126-6.10.1016/S0387-7604(99)00126-610722962Pane M., Messina S., Bruno C., D’Amico A., Villanova M., Brancalion B., Sivo S., Bianco F., Striano P., Battaglia D., et al. Duchenne muscular dystrophy and epilepsy. Neuromuscul. Disord. 2013;23:313–315. doi: 10.1016/j.nmd.2013.01.011.10.1016/j.nmd.2013.01.01123465656Leiden Muscular Dystrophy pages. [(accessed on 11 June 2017)]; Available online: http://www.dmd.nl/DMD_home.html.Chiurazzi P., Schwartz C.E., Gecz J., Neri G. XLMR genes: Update 2007. Eur. J. Hum. Genet. 2008;16:422–434. doi: 10.1038/sj.ejhg.5201994.10.1038/sj.ejhg.520199418197188Felisari G., Martinelli Boneschi F., Bardoni A., Sironi M., Comi G.P., Robotti M., Turconi A.C., Lai M., Corrao G., Bresolin N. Loss of Dp140 dystrophin isoform and intellectual impairment in Duchenne dystrophy. Neurology. 2000;55:559–564. doi: 10.1212/WNL.55.4.559.10.1212/WNL.55.4.55910953192Taylor P.J., Betts G.A., Maroulis S., Gilissen C., Pedersen R.L., Mowat D.R., Johnston H.M., Buckley M.F. Dystrophin gene mutation location and the risk of cognitive impairment in Duchenne muscular dystrophy. PLoS ONE. 2010;5:e8803. doi: 10.1371/journal.pone.0008803.10.1371/journal.pone.0008803PMC280835920098710Wingeier K., Giger E., Strozzi S., Kreis R., Joncourt F., Conrad B., Gallati S., Steinlin M. Neuropsychological impairments and the impact of dystrophin mutations on general cognitive functioning of patients with Duchenne muscular dystrophy. J. Clin. Neurosci. 2011;18:90–95. doi: 10.1016/j.jocn.2010.07.118.10.1016/j.jocn.2010.07.11821109441Ricotti V., Mandy W.P., Scoto M., Pane M., Deconinck N., Messina S., Mercuri E., Skuse D.H., Muntoni F. Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations. Dev. Med. Child Neurol. 2016;58:77–84. doi: 10.1111/dmcn.12922.10.1111/dmcn.1292226365034Mazzeo A., Rodolico C., Monici M.C., Migliorato A., Aguennouz M., Vita G. Perineurium talin immunoreactivity decreases in diabetic neuropathy. J. Neurol. Sci. 1997;146:7–11. doi: 10.1016/S0022-510X(96)00285-7.10.1016/S0022-510X(96)00285-79077489Sanders A.E., Jain D., Sofer T., Kerr K.F., Laurie C.C., Shaffer J.R., Marazita M.L., Kaste L.M., Slade G.D., Fillingim R.B., et al. GWAS identifies new loci for painful temporomandibular disorder: Hispanic Community Health Study/Study of Latinos. J. Dent. Res. 2017;96:277–284. doi: 10.1177/0022034516686562.10.1177/0022034516686562PMC529839728081371BLAST Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information. [(accessed on 11 June 2017)]; Available online: https://blast.ncbi.nlm.nih.gov/Blast.cgi.Kozak M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucleic Acids Res. 1984;12:857–872. doi: 10.1093/nar/12.2.857.10.1093/nar/12.2.857PMC3185416694911TIS miner. [(accessed on 11 June 2017)]; Available online: http://dnafsminer.bic.nus.edu.sg/Tis.html.Liu H., Wong L. Data mining tools for biological sequences. J. Bioinform. Comput. Biol. 2003;1:139–167. doi: 10.1142/S0219720003000216.10.1142/S021972000300021615290785Gonzalez-Noriega A., Michalak C., Cervantes-Roldan R., Gomez-Romero V., Leon-Del-Rio A. Two translation initiation codons direct the expression of annexin VI 64kDa and 68kDa isoforms. Mol. Genet. Metab. 2016;119:338–343. doi: 10.1016/j.ymgme.2016.10.002.10.1016/j.ymgme.2016.10.00227743858Jin H., Tan S., Hermanowski J., Bohm S., Pacheco S., McCauley J.M., Greener M.J., Hinits Y., Hughes S.M., Sharpe P.T., et al. The dystrotelin, dystrophin and dystrobrevin superfamily: New paralogues and old isoforms. BMC Genomics. 2007;8:19. doi: 10.1186/1471-2164-8-19.10.1186/1471-2164-8-19PMC179070917233888Tarnow P., Schoneberg T., Krude H., Gruters A., Biebermann H. Mutationally induced disulfide bond formation within the third extracellular loop causes melanocortin 4 receptor inactivation in patients with obesity. J. Biol. Chem. 2003;278:48666–48673. doi: 10.1074/jbc.M309941200.10.1074/jbc.M30994120014504270Hanggi E., Grundschober A.F., Leuthold S., Meier P.J., St-Pierre M.V. Functional analysis of the extracellular cysteine residues in the human organic anion transporting polypeptide, OATP2B1. Mol. Pharmacol. 2006;70:806–817. doi: 10.1124/mol.105.019547.10.1124/mol.105.01954716754786Judge L.M., Haraguchiln M., Chamberlain J.S. Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex. J. Cell Sci. 2006;119:1537–1546. doi: 10.1242/jcs.02857.10.1242/jcs.0285716569668