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Smith–Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways

  • Sarah H. Elsea (a1) (a2) and Stephen R. Williams (a2)

Smith–Magenis syndrome (SMS) is a complex neurobehavioural disorder characterised by intellectual disability, self-injurious behaviours, sleep disturbance, obesity, and craniofacial and skeletal anomalies. Diagnostic strategies are focused towards identification of a 17p11.2 microdeletion encompassing the gene RAI1 (retinoic acid induced 1) or a mutation of RAI1. Molecular evidence shows that most SMS features are due to RAI1 haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region for 17p11.2 deletion cases. The functional role of RAI1 is not completely understood, but it is probably a transcription factor acting in several different biological pathways that are dysregulated in SMS. Functional studies based on the hypothesis that RAI1 acts through phenotype-specific pathways involving several downstream genes have shown that RAI1 gene dosage is crucial for normal regulation of circadian rhythm, lipid metabolism and neurotransmitter function. Here, we review the clinical and molecular features of SMS and explore more recent studies supporting possible therapeutic strategies for behavioural management.

Corresponding author
*Corresponding author: Sarah H. Elsea, Department of Pediatrics, 1101 E. Marshall Street, 12-018 Sanger Hall, VCU School of Medicine, Richmond, VA 23298, USA. E-mail:
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Expert Reviews in Molecular Medicine
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