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J Pediatr Genet 2017; 06(03): 155-164
DOI: 10.1055/s-0037-1599147
Original Article
Georg Thieme Verlag KG Stuttgart · New York

RAI1 Overexpression Promotes Altered Circadian Gene Expression and Dyssomnia in Potocki–Lupski Syndrome

Sureni V. Mullegama   *
1   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
2   Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, United States
,
Joseph T. Alaimo   *
1   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
,
Michael D. Fountain   *
1   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
,
Brooke Burns
3   Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States
,
Amanda Hebert Balog
3   Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States
,
Li Chen
1   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
4   Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
,
Sarah H. Elsea
1   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
2   Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, United States
3   Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States
› Author Affiliations
Further Information

Publication History

22 November 2016

17 January 2017

Publication Date:
07 March 2017 (online)

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Abstract

Retinoic acid induced 1 (RAI1) encodes a dosage-sensitive gene that when haploinsufficient results in Smith–Magenis syndrome (SMS) and when overexpressed results in Potocki–Lupski syndrome (PTLS). Phenotypic and molecular evidence illustrates that haploinsufficiency of RAI1 disrupts circadian rhythm through the dysregulation of the master circadian regulator, circadian locomotor output cycles kaput (CLOCK), and other core circadian components, contributing to prominent sleep disturbances in SMS. However, the phenotypic and molecular characterization of sleep features in PTLS has not been elucidated. Using the Pittsburgh Sleep Quality Index (PSQI), caregivers of 15 school-aged children with PTLS reported difficulties in initiating sleep. Indeed, more than 70% of individuals manifested moderate to severe sleep latency, as defined by the PSQI. Moreover, these individuals manifested difficulties in sleep maintenance, with middle of the night and early morning awakenings. When assessing daytime sleepiness through the Epworth Sleepiness Scale, approximately 21% of the individuals manifested excessive daytime somnolence. This indicates that mild dyssomnia characterizes the majority of the sleep phenotype, with occasionally problematic daytime somnolence, a phenotype different than that expressed by individuals with SMS, where daytime sleepiness is a chronic problem. Gene expression analysis of the core circadian machinery in the hypothalamus of the PTLS mouse model (Rai1-Tg) found significant dysregulation of the transcriptional activators, Clock and Arntl, and the transcriptional repressors, Per1–3 and Cry1/2, during both light and dark phases. These findings suggest a partial loss of circadian entrainment typically evoked by environmental photic cues. Examination of circadian clock gene expression in the Rai1-Tg mouse heart, liver, and kidney found unchanged expression of Clock and most of its downstream targets during both light and dark phases, suggesting an asynchronized circadian rhythm. Furthermore, examination of circadian gene expression in synchronized PTLS lymphoblasts revealed reduced transcripts of the Period (PER1–3) family and normal expression of CRY1/2. The finding that central circadian gene expression was altered while many peripheral circadian components were intact suggests a tissue-specific circadian uncoupling of the circadian machinery due to Rai1 overexpression. Overall, our results demonstrate that overexpression of RAI1 results in sleep deficiencies in individuals with PTLS due to a lack of properly regulated circadian machinery gene expression and highlight the importance of evaluating sleep concerns in individuals with PTLS.

Keywords

Potocki–Lupski syndrome - RAI1 - circadian rhythm - sleep disturbance

* Authors contributed equally to this work.


Supplementary Material

 

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