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Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes

Mullegama, Sureni V. and Klein, Steven D. and Williams, Stephen R. and Innis, Jeffrey W. and Probst, Frank J. and Haldeman-Englert, Chad and Martinez-Agosto, Julian A. and Yang, Ying and Tian, Yuchen and Elsea, Sarah H. and Ezashi, Toshihiko (2021) Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes. Scientific Reports, 11 . Art. No. 11295. ISSN 2045-2322.

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MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) characterized by intellectual disability, motor delay, speech impairment and behavioral problems; however, the biological role of methyl-CpG-binding domain 5, MBD5, in neurodevelopment and ASD remains largely undefined. Hence, we created neural progenitor cells (NPC) derived from individuals with chromosome 2q23.1 deletion and conducted RNA-seq to identify differentially expressed genes (DEGs) and the biological processes and pathways altered in MAND. Primary skin fibroblasts from three unrelated individuals with MAND and four unrelated controls were converted into induced pluripotent stem cell (iPSC) lines, followed by directed differentiation of iPSC to NPC. Transcriptome analysis of MAND NPC revealed 468 DEGs (q < 0.05), including 20 ASD-associated genes. Comparison of DEGs in MAND with SFARI syndromic autism genes revealed a striking significant overlap in biological processes commonly altered in neurodevelopmental phenotypes, with TGFβ, Hippo signaling, DNA replication, and cell cycle among the top enriched pathways. Overall, these transcriptome deviations provide potential connections to the overlapping neurocognitive and neuropsychiatric phenotypes associated with key high-risk ASD genes, including chromatin modifiers and epigenetic modulators, that play significant roles in these disease states.

Item Type:Article
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URLURL TypeDescription
Mullegama, Sureni V.0000-0001-5780-2803
Klein, Steven D.0000-0001-8634-0388
Martinez-Agosto, Julian A.0000-0001-6776-6949
Elsea, Sarah H.0000-0002-1400-8519
Ezashi, Toshihiko0000-0001-6955-8449
Additional Information:© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Received 24 June 2020. Accepted 20 April 2021. Published 28 May 2021. We are grateful to the study participants and their families for their cooperation in this study. We thank the N.J. Bivens in the DNA core at University of Missouri, Columbia (UMC) for RNA sequencing and Dr. Janice Smith and her team for assistance with CMAs. The work was supported, in part, by the resources from University of California, Los Angeles, Bond Life Sciences Center at UMC, Baylor College of Medicine, University of Michigan, and Jan and Duncan Neurological Research Institute at the Texas Children’s Hospital. JWI acknowledges support from the Morton S. and Henrietta K. Sellner Professorship in Human Genetics. The PAX6 monoclonal antibody developed by Kawakami, A. with the N-terminal region, aa 1-223 was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242. The following cell lines were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research: GM05659 and GM24585. We thank Mr. Dennis Reith for editorial assistance. This work was supported by grants from Patton Trust Research Grant program at the Kansas City Area Life Sciences Institute (TE), Fondation Jérôme Lejeune (SHE), March of Dimes (Grant #6-FY12-324, JAM-A), UCLA Children’s Discovery Institute, UCLA CART (NIH/NICHD Grant# P50-HD-055784, JAM-A), NIH/NCATS UCLA CTSI (Grant # UL1TR000124, JAM-A), Autism Speaks Grant #9172 (SK) and the UCLA-Caltech MSTP NIH T32GM008042 (SK). Data availability. The RNA-seq data are available in the Gene Expression Omnibus (GSE141835). The authors declare no competing interests.
Funding AgencyGrant Number
Patton Trust ResearchUNSPECIFIED
Kansas City Area Life Sciences InstituteUNSPECIFIED
Fondation Jérôme LejeuneUNSPECIFIED
March of Dimes Foundation6-FY12-324
UCLA Children’s Discovery InstituteUNSPECIFIED
Autism Speaks9172
NIH Predoctoral FellowshipT32GM008042
Record Number:CaltechAUTHORS:20210528-094921843
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Official Citation:Mullegama, S.V., Klein, S.D., Williams, S.R. et al. Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes. Sci Rep 11, 11295 (2021).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109294
Deposited By: George Porter
Deposited On:28 May 2021 17:30
Last Modified:28 May 2021 17:30

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