Common molecular networks in Rett, Angelman, Smith-Magenis, Potocki-Lupski, Pitt-Hopkins, and chromosome 2q23.1 deletion syndromes contribute to intellectual disability, seizures, sleep, language, behavior and autism spectrum disorder. S. V. Mullegama1,2, B. Burns2, Z. Shah2, R. Tahir2, W.-H. Tan3, S. H. Elsea1,2,4 1) Human and Molecular Genetics, Baylor College of Medicine, Houston , TX; 2) Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA; 3) Division of Genetics, Boston Childrens Hospital, Boston, MA, USA; 4) Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

   Chromatin modifying genes play important roles in the genetic etiology of neurodevelopmental disorders (NDs). Many monogenic NDs are caused by altered dosage of chromatin modifying genes, including Rett (RTT, MECP2), Angelman (AS, UBE3A), Smith-Magenis (SMS, RAI1), Potocki-Lupski (PTLS, RAI1), Pitt-Hopkins (PTHS, TCF4), and 2q23.1 del/dup syndromes (MBD5). NDs are genetically and phenotypically heterogeneous but share common features that include intellectual disability with severe language delay, autism spectrum disorder, sleep disturbances, and behavioral difficulties; however, the molecular mechanisms responsible for these associations remain unknown. To investigate whether common networks are dysregulated resulting in these overlapping features, we evaluated expression of the 5 causative genes for these disorders in disorder-specific cell lines and patient lymphocyte samples, as well as gene expression microarrays of cell lines with gene-specific knockdown. QPCR studies revealed altered expression of MECP2, UBE3A, RAI1, MBD5, and TCF4 in these cell lines. All genes had significantly reduced expression in RTT lines, which suggests a hierarchy of genes, with MECP2 dosage highly critical for normal expression of these genes. Reduced expression of UBE3A in SMS lines and its overexpression in PTLS lines suggests UBE3A expression is sensitive to RAI1 dosage, which is corroborated by our ChIP-chip studies that indicate RAI1 directly binds to the UBE3A promoter. Expression of RAI1 is reduced in both 2q23.1 disorders suggesting possible regulation of RAI1 by MBD5. Furthermore, knockdown of MBD5 and RAI1 in neuroblastoma cell lines revealed dysregulation of known autism-linked genes, including MLL3, PLAUR, TBX1, HDAC10, SMARCB1, and ABAT, as well as other chromatin modifying genes. Pathway analyses showed that MBD5 and RAI1 function in chromatin remodeling, neuronal development, and cell growth/survival pathways. Two pathways disrupted by haploinsuffiiciency of RAI1 and MBD5 were the mTOR and circadian rhythm signaling pathways associated with autism and sleep phenotypes, respectively. Overall, these data suggest the presence of interconnected neurodevelopmental networks that when impacted by changes in gene expression may result in overlapping features across these syndromes. Identifying common points of regulation in these pathways may lead to therapeutic intervention for treatment of the common phenotypes, including sleep and behavioral problems.

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