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Longitudinal dystrophin gene expression from the fetal to adult human brain correlates with genes linked to ausm spectrum disorders and intellectual disabilityAhmed Mahfouz1,2 & Nathalie Doorenweerd3,4,6 (equal contribuon), Maaike van Puen5, Rajaram Kaliyaperumal5, Peter A.C. ’t Hoen5, Jan J.G.M. Verschuuren4, Erik H. Niks4, Marcel J.T. Reinders2, Hermien E. Kan3,5, Boudewijn P.F. Lelieveldt1
1Division of Image Processing, Department of Radiology, LUMC; 2Del Bioinformacs Lab, TU Del; 3C.J. Gorter Centre for High Field MRI, Department of Radiology, LUMC; 4Department of Neurology, LUMC; 5Department of Human Genecs, LUMC; 6Leiden Instute for Brain and Cognion, Leiden University
SummaryIn addion to skeletal muscle pathology, Duchenne muscular dystrophy (DMD) is characterized by cognive and behavioural problems as well as altered brain morphology. These are more substanal in paents with a DMD gene mutaon affecng the expression of various shorter dystrophin isoforms in the brain. In this study, we aim to provide detailed understanding of the localizaon and funcon of the different DMD isoforms throughout brain development.UsingUsing the developing human brain transcriptome data from the BrainSpan1 Atlas, we analyzed the expression of the unique first exons of the diffirent DMD isoforms (Dp427(p,c,m), Dp260, Dp140, Dp116 and the shared first exon of Dp71 and Dp40) across the brain and throughout human development. In addion, we used the Allen Human Brain Atlas2 to analyze the expression of the DMD gene at a higher resoluon across different brain structures. Finally, we assessed the list of genes co-expressed with the didifferent DMD isoforms across development for enrichment in genes implicated in ausm spectrum disorders (ASD) and intellectual disability (ID).
BrainSpan Atlas524 ssue samples RNA-seq, expression per exon (RPKM)
6 adult donors (5 males & 1 female; mean age 42, range 24-57 years)363 to 946 different samples per brain (3,702 samples in total) Microarray gene expression (only Dp140bc; no other isoforms)
Allen Human Brain Atlas
Genes co-expressed with DMD are enriched in genes related to ASD & ID
DMD Isoforms Across Development
Adult DMD Expression
Dp427 Dp140 Dp71 & Dp40
Associaon with developmental disorders
Results of the longitudinal isoform expression suggest that Dp71+Dp40 could be a potenal post-natal therapeuc target more than Dp140. The enriched co-expression provides a genec link that might explain the high incidence of ASD and ID in DMD. Knowledge from these genes may lead to a beer understanding of the funcon of dystrophin in the brain.
Conclusions
References1Miller J a, et al. (2014) Transcriponal landscape of the prenatal human brain. Nature 508(7495):199–206.2Hawrylycz MJ, et al. (2012) An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489(7416):391–9.
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