MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes

• Published in: European journal of human genetics : EJHG Vol. 23; no. 6; pp. 781 - 789
• Main Authors: Mullegama, Sureni V, Pugliesi, Loren, Burns, Brooke, Shah, Zalak, Tahir, Raiha, Gu, Yanghong, Nelson, David L, Elsea, Sarah H
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2015
• Subjects: Autism; Behavior; Cell Line; Child; Child, Preschool; Circadian rhythm; Circadian Rhythm - genetics; Circadian rhythms; Clonal deletion; Cryptochromes - genetics; Cryptochromes - metabolism; DNA microarrays; DNA-Binding Proteins - genetics; Female; FMR1 protein; Fragile X mental retardation protein; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X syndrome; Fragile X Syndrome - genetics; Gene expression; Genetic counseling; Genetics; Haploinsufficiency; Humans; Infant; Intellectual disabilities; Lymphoblastoid cell lines; Male; Medicine; Melatonin; Metabolism; Neurodevelopmental disorders; Period 1 protein; Period 2 protein; Period 3 protein; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; Phenotype; Phenotypes; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction; siRNA; Sleep; Sleep Wake Disorders - genetics; Smith-Magenis Syndrome - genetics; Support groups; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; United States > US
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2014.200

Individuals with autism spectrum disorders (ASD) who have an identifiable single-gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith-Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders.