title: MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Sureni V
authors.initials: SV
authors.lastname: Mullegama
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Loren
authors.initials: L
authors.lastname: Pugliesi
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Brooke
authors.initials: B
authors.lastname: Burns
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Zalak
authors.initials: Z
authors.lastname: Shah
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Raiha
authors.initials: R
authors.lastname: Tahir
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yanghong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.affiliation: 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA [2] Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Elsea
mesh_terms: D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D008297:Male; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012893:Sleep Wake Disorders / Q000235:genetics*; D058496:Smith-Magenis Syndrome / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D056931:Cryptochromes; D004268:DNA-Binding Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D056950:Period Circadian Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; C538966:CRY2 protein, human; C497683:FMR1 protein, human; C550332:MBD5 protein, human; C090977:NR1D2 protein, human; C431552:RAI1 protein, human