289747272019062520190625
2045-2322712017Oct03Scientific reportsSci RepTiming and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy.12575125751257510.1038/s41598-017-12981-5Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.DoorenweerdNathalieNC.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. N.Doorenweerd@lumc.nl.Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. N.Doorenweerd@lumc.nl.Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands. N.Doorenweerd@lumc.nl.John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle Upon Tyne, United Kingdom. N.Doorenweerd@lumc.nl.MahfouzAhmedA0000-0001-8601-2149Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.van PuttenMaaikeMDepartment of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.KaliyaperumalRajaramRDepartment of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.T' HoenPeter A CPACDepartment of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.HendriksenJos G MJGMDepartment of Neurological Learning Disabilities, Kempenhaeghe Epilepsy Center, Heeze, The Netherlands.Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.Aartsma-RusAnnemieke MAMDepartment of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.VerschuurenJan J G MJJGM0000-0002-4572-1501Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.NiksErik HEHDepartment of Neurology, Leiden University Medical Center, Leiden, The Netherlands.ReindersMarcel J TMJT0000-0002-1148-1562Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.KanHermien EHEC.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands.LelieveldtBoudewijn P FBPF0000-0001-8269-7603Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.engJournal ArticleResearch Support, Non-U.S. Gov't20171003
EnglandSci Rep1015632882045-23220Dystrophin0Protein IsoformsIMSci Rep. 2018 Mar 1;8(1):4058. doi: 10.1038/s41598-018-22154-7.29497163Autism Spectrum DisordergeneticsmetabolismphysiopathologyAxonsmetabolismCell DifferentiationgeneticsCerebral Cortexgrowth & developmentmetabolismDystrophingeneticsFetusmetabolismGene Expression Regulation, DevelopmentalgeneticsHumansMuscular Dystrophy, DuchennegeneticsmetabolismphysiopathologyMutationNeuronsmetabolismNeuropsychological TestsPhenotypeProtein IsoformsgeneticsPurkinje CellsmetabolismpathologyTranscriptomegeneticsThe authors declare that they have no competing interests.20172120179132017105602017105602019627602017103epublish28974727PMC562677910.1038/s41598-017-12981-510.1038/s41598-017-12981-5Cotton S, Voudouris NJ, Greenwood KM. Intelligence and Duchenne muscular dystrophy: full-scale, verbal, and performance intelligence quotients. Dev. Med. Child Neurol. 2001;43:497–501. doi: 10.1017/S0012162201000913.10.1017/S001216220100091311463183Billard C, et al. Cognitive functions in Duchenne muscular dystrophy: a reappraisal and comparison with spinal muscular atrophy. Neuromuscul. Disord. 1992;2:371–378. doi: 10.1016/S0960-8966(06)80008-8.10.1016/S0960-8966(06)80008-81300185Dorman C, Hurley AD, D’Avignon J. Language and learning disorders of older boys with Duchenne muscular dystrophy. Dev.Med. Child Neurol. 1988;30:316–327. doi: 10.1111/j.1469-8749.1988.tb14556.x.10.1111/j.1469-8749.1988.tb14556.x3402673Castles A, Coltheart M. Varieties of developmental dyslexia. Cognition. 1993;47:149–80. doi: 10.1016/0010-0277(93)90003-E.10.1016/0010-0277(93)90003-E8324999Banihani R, et al. Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy. J. Child Neurol. 2015;30:1472–1482. doi: 10.1177/0883073815570154.10.1177/088307381557015425660133Pane M, 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.2013.01.01123465656Hendriksen JG, Vles JS. Neuropsychiatric disorders in males with duchenne muscular dystrophy: frequency rate of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, and obsessive–compulsive disorder. J. Child Neurol. 2008;23:477–481. doi: 10.1177/0883073807309775.10.1177/088307380730977518354150Pane M, et al. Early neurodevelopmental assessment in Duchenne muscular dystrophy. Neuromuscul.Disord. 2013;23:451–455. doi: 10.1016/j.nmd.2013.02.012.10.1016/j.nmd.2013.02.01223535446Yoshioka M, Okuno T, Honda Y, Nakano Y. Central nervous system involvement in progressive muscular dystrophy. Arch. Dis. Child. 1980;55:589–94. doi: 10.1136/adc.55.8.589.10.1136/adc.55.8.589PMC16270647436514Young HK, et al. Cognitive and psychological profile of males with Becker muscular dystrophy. J. Child Neurol. 2008;23:155–162. doi: 10.1177/0883073807307975.10.1177/088307380730797518056690Goodwin F, Muntoni F, Dubowitz V. Epilepsy in Duchenne and Becker muscular dystrophies. Eur. J. Paediatr. Neurol. 1997;1:115–119. doi: 10.1016/S1090-3798(97)80042-6.10.1016/S1090-3798(97)80042-610728205Sweeney HL, Barton ER. The dystrophin-associated glycoprotein complex: what parts can you do without? Proc. Natl. Acad. Sci. USA. 2000;97:13464–13466. doi: 10.1073/pnas.011510597.10.1073/pnas.011510597PMC3408011095702Townsend D. Finding the sweet spot: assembly and glycosylation of the dystrophin-associated glycoprotein complex. Anat. Rec.(Hoboken.) 2014;297:1694–1705. doi: 10.1002/ar.22974.10.1002/ar.22974PMC413552325125182Waite A, Brown SC, Blake DJ. The dystrophin-glycoprotein complex in brain development and disease. Trends Neurosci. 2012;35:487–496. doi: 10.1016/j.tins.2012.04.004.10.1016/j.tins.2012.04.00422626542Hendriksen RGF, et al. Dystrophin Distribution and Expression in Human and Experimental Temporal Lobe Epilepsy. Front. Cell. Neurosci. 2016;10:174. doi: 10.3389/fncel.2016.00174.10.3389/fncel.2016.00174PMC493701627458343Nudel U, et al. Duchenne Muscular-Dystrophy Gene-Product Is Not Identical in Muscle and Brain. Nature. 1989;337:76–78. doi: 10.1038/337076a0.10.1038/337076a02909892Lidov et al. Localization of dystrophin to postsynaptic regions of the central nervous system cortical neurons.pdf (2000).2259381Holder E, Maeda M, Bies RD. Expression and regulation of the dystrophin Purkinje promoter in human skeletal muscle, heart, and brain. Hum. Genet. 1996;97:232–239. doi: 10.1007/BF02265272.10.1007/BF022652728566960Dsouza VN, et al. A Novel Dystrophin Isoform Is Required for Normal Retinal Electrophysiology. Hum. Mol. Genet. 1995;4:837–842. doi: 10.1093/hmg/4.5.837.10.1093/hmg/4.5.8377633443Byers TJ, Lidov HGW, Kunkel LM. An Alternative Dystrophin Transcript Specific to Peripheral-Nerve. Nat. Genet. 1993;4:77–81. doi: 10.1038/ng0593-77.10.1038/ng0593-778513330Morris GE, Simmons C, Man NT. Apo-Dystrophins (Dp140 and Dp71) and Dystrophin Splicing Isoforms in Developing Brain. Biochem. Biophys. Res. Commun. 1995;215:361–367. doi: 10.1006/bbrc.1995.2474.10.1006/bbrc.1995.24747575614Lederfein D, et al. A 71-kilodalton protein is a major product of the Duchenne muscular dystrophy gene in brain and other nonmuscle tissues. Proc. Natl. Acad. Sci. USA. 1992;89:5346–5350. doi: 10.1073/pnas.89.12.5346.10.1073/pnas.89.12.5346PMC492881319059Austin RC, Howard PL, D’Souza VN, Klamut HJ, Ray PN. Cloning and characterization of alternatively spliced isoforms of Dp71. Hum. Mol. Genet. 1995;4:1475–1483. doi: 10.1093/hmg/4.9.1475.10.1093/hmg/4.9.14758541829Taylor, P. J. et al. Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy. PLoS One5 (2010).PMC280835920098710Chamova T, et al. Association Between Loss of Dp140 and Cognitive Impairment in Duchenne and Becker Dystrophies. Balk. J. Med. Genet. 2013;16:21–29.PMC383529324265581Ricotti, V. et al. Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations. Dev. Med. Child Neurol. (2015).26365034Doorenweerd N, 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.2422225043804Miller JA, et al. Transcriptional landscape of the prenatal human brain. Nature. 2014;508:199–206. doi: 10.1038/nature13185.10.1038/nature13185PMC410518824695229Gorecki DC, et al. Expression of 4 Alternative Dystrophin Transcripts in Brain-Regions Regulated by Different Promoters. Hum. Mol. Genet. 1992;1:505–510. doi: 10.1093/hmg/1.7.505.10.1093/hmg/1.7.5051307251Kueh SLL, Head SI, Morley JW. GABA(A) receptor expression and inhibitory post-synaptic currents in cerebellar Purkinje cells in dystrophin-deficient mdx mice. Clin. Exp. Pharmacol. Physiol. 2008;35:207–10.17941889Snow WM, Anderson JE, Fry M. Regional and genotypic differences in intrinsic electrophysiological properties of cerebellar Purkinje neurons from wild-type and dystrophin-deficient mdx mice. Neurobiol. Learn. Mem. 2014;107:19–31. doi: 10.1016/j.nlm.2013.10.017.10.1016/j.nlm.2013.10.01724220092Lidov HG, Selig S, Kunkel LM. Dp140: a novel 140 kDa CNS transcript from the dystrophin locus. Hum. Mol. Genet. 1995;4:329–35. doi: 10.1093/hmg/4.3.329.10.1093/hmg/4.3.3297795584Lidov HGW, Byers TJ, Kunkel LM. The Distribution of Dystrophin in the Murine Central-Nervous-System - An Immunocytochemical Study. Neuroscience. 1993;54:167–187. doi: 10.1016/0306-4522(93)90392-S.10.1016/0306-4522(93)90392-S8515841Snow WM, Fry M, Anderson JE. Increased density of dystrophin protein in the lateral versus the vermal mouse cerebellum. Cell Mol. Neurobiol. 2013;33:513–520. doi: 10.1007/s10571-013-9917-8.10.1007/s10571-013-9917-8PMC1149798123436181Lenhard B, Sandelin A, Carninci P. Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nat. Rev. Genet. 2012;13:233–245. doi: 10.1038/nrg3163.10.1038/nrg316322392219Lizio M, et al. Gateways to the FANTOM5 promoter level mammalian expression atlas. Genome.Biol. 2015;16:22. doi: 10.1186/s13059-014-0560-6.10.1186/s13059-014-0560-6PMC431016525723102Forrest AR, et al. A promoter-level mammalian expression atlas. Nature. 2014;507:462–470. doi: 10.1038/nature13182.10.1038/nature13182PMC452974824670764Kundaje A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–330. doi: 10.1038/nature14248.10.1038/nature14248PMC453001025693563Stuart JM, Segal E, Koller D, Kim SK. A gene-coexpression network for global discovery of conserved genetic modules. Science (80-.). 2003;302:249–255. doi: 10.1126/science.1087447.10.1126/science.108744712934013Pinero J, et al. DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes. Database. (Oxford) 2015;2015:bav028. doi: 10.1093/database/bav028.10.1093/database/bav028PMC439799625877637Lidov, H. G. W. Dystrophin in the Nervous System. Brain Pathol. 63–77.8866748Zeisel A, et al. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science (80-.). 2015;347:1138–42. doi: 10.1126/science.aaa1934.10.1126/science.aaa193425700174Tasic B, et al. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat. Neurosci. 2016;advance on:1–37.PMC498524226727548Ricotti, V. et al. Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system. Eur. J. Hum. Genet. (2015).PMC492986326081639Liu Y, et al. On the Dependency of Cellular Protein Levels on mRNA Abundance. Cell. 2016;165:535–550. doi: 10.1016/j.cell.2016.03.014.10.1016/j.cell.2016.03.01427104977Cyrulnik SE, Hinton VJ. Duchenne muscular dystrophy: a cerebellar disorder? Neurosci. Biobehav. Rev. 2008;32:486–96. doi: 10.1016/j.neubiorev.2007.09.001.10.1016/j.neubiorev.2007.09.00118022230Fatemi SH, et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum. 2012;11:777–807. doi: 10.1007/s12311-012-0355-9.10.1007/s12311-012-0355-9PMC367755522370873Chaussenot R, et al. Cognitive dysfunction in the dystrophin-deficient mouse model of Duchenne muscular dystrophy: A reappraisal from sensory to executive processes. Neurobiol. Learn. Mem. 2015;124:111–122. doi: 10.1016/j.nlm.2015.07.006.10.1016/j.nlm.2015.07.00626190833Vaillend C, Billard JM, Laroche S. Impaired long-term spatial and recognition memory and enhanced CA1 hippocampal LTP in the dystrophin-deficient Dmd(mdx) mouse. Neurobiol. Dis. 2004;17:10–20. doi: 10.1016/j.nbd.2004.05.004.10.1016/j.nbd.2004.05.00415350961Doorenweerd N, et al. G.P.127 Reduced cerebral blood flow in boys with Duchenne muscular dystrophy. in. Neuromuscular Disorders. 2014;24:838–839.Krumm N, O’Roak BJ, Shendure J, Eichler EE. A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci. 2014;37:95–105. doi: 10.1016/j.tins.2013.11.005.10.1016/j.tins.2013.11.005PMC407778824387789Goodnough CL, et al. Lack of dystrophin results in abnormal cerebral diffusion and perfusion in vivo. Neuroimage. 2014;102(Pt 2):809–16. doi: 10.1016/j.neuroimage.2014.08.053.10.1016/j.neuroimage.2014.08.053PMC432094325213753Lim KR, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des. Devel. Ther. 2017;ume11:533–545. doi: 10.2147/DDDT.S97635.10.2147/DDDT.S97635PMC533884828280301Haas M, et al. European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene. Neuromuscul. Disord. 2015;25:5–13. doi: 10.1016/j.nmd.2014.11.011.10.1016/j.nmd.2014.11.01125497400Syed YY. Eteplirsen: First Global Approval. Drugs. 2016;76:1699–1704. doi: 10.1007/s40265-016-0657-1.10.1007/s40265-016-0657-127807823Wang J-Z, Wu P, Shi Z-M, Xu Y-L, Liu Z-J. The AAV-mediated and RNA-guided CRISPR/Cas9 system for gene therapy of DMD and BMD. Brain Dev. 201728390761Goyenvalle A, et al. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat. Med. 2015;21:270–5. doi: 10.1038/nm.3765.10.1038/nm.376525642938Wheway JM, Roberts RG. The dystrophin lymphocyte promoter revisited: 4.5-megabase intron, or artifact? Neuromuscul.Disord. 2003;13:17–20. doi: 10.1016/S0960-8966(02)00195-5.10.1016/S0960-8966(02)00195-512467728Hawrylycz MJ, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012;489:391–399. doi: 10.1038/nature11405.10.1038/nature11405PMC424302622996553Bladen CL, et al. The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations. Hum. Mutat. 2015;36:395–402. doi: 10.1002/humu.22758.10.1002/humu.22758PMC440504225604253Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 2009;37:W305–W311. doi: 10.1093/nar/gkp427.10.1093/nar/gkp427PMC270397819465376Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav.Brain Res. 2001;125:279–284. doi: 10.1016/S0166-4328(01)00297-2.10.1016/S0166-4328(01)00297-211682119Iossifov I, et al. De novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74:285–299. doi: 10.1016/j.neuron.2012.04.009.10.1016/j.neuron.2012.04.009PMC361997622542183Neale BM, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242–245. doi: 10.1038/nature11011.10.1038/nature11011PMC361384722495311O’Roak BJ, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485:246–250. doi: 10.1038/nature10989.10.1038/nature10989PMC335057622495309Sanders SJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–241. doi: 10.1038/nature10945.10.1038/nature10945PMC366798422495306de LJ, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 2012;367:1921–1929. doi: 10.1056/NEJMoa1206524.10.1056/NEJMoa120652423033978Rauch A, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674–1682. doi: 10.1016/S0140-6736(12)61480-9.10.1016/S0140-6736(12)61480-923020937Hormozdiari F, Penn O, Borenstein E, Eichler EE. The discovery of integrated gene networks for autism and related disorders. Genome. Res. 2015;25:142–154. doi: 10.1101/gr.178855.114.10.1101/gr.178855.114PMC431717025378250Basu SN, Kollu R, Banerjee-Basu S. AutDB: a gene reference resource for autism research. Nucleic Acids Res. 2009;37:D832–D836. doi: 10.1093/nar/gkn835.10.1093/nar/gkn835PMC268650219015121Zhou X, et al. The Human Epigenome Browser at Washington University. Nat. Methods. 2011;8:989–990. doi: 10.1038/nmeth.1772.10.1038/nmeth.1772PMC355264022127213Ruijter JM, et al. Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res. 2009;37:e45. doi: 10.1093/nar/gkp045.10.1093/nar/gkp045PMC266523019237396