Sleep fragmentation and motor restlessness in a Drosophila model of Restless Legs Syndrome

Curr Biol. 2012 Jun 19;22(12):1142-8. doi: 10.1016/j.cub.2012.04.027. Epub 2012 May 31.


Restless Legs Syndrome (RLS), first chronicled by Willis in 1672 and described in more detail by Ekbom in 1945, is a prevalent sensorimotor neurological disorder (5%-10% in the population) with a circadian predilection for the evening and night. Characteristic clinical features also include a compelling urge to move during periods of rest, relief with movement, involuntary movements in sleep (viz., periodic leg movements of sleep), and fragmented sleep. Although the pathophysiology of RLS is unknown, dopaminergic neurotransmission and deficits in iron availability modulate expressivity. Genome-wide association studies have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS. Here, we report that loss of the Drosophila homolog CG1826 (dBTBD9) appreciably disrupts sleep with concomitant increases in waking and motor activity. We further show that BTBD9 regulates brain dopamine levels in flies and controls iron homeostasis through the iron regulatory protein-2 in human cell lines. To our knowledge, this represents the first reverse genetic analysis of a "novel" or heretofore poorly understood gene implicated in an exceedingly common and complex sleep disorder and the development of an RLS animal model that closely recapitulates all disease phenotypes.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Brain / metabolism*
  • Carrier Proteins / genetics*
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Dopamine / metabolism*
  • Drosophila
  • Drosophila Proteins / genetics*
  • Genetic Vectors / genetics
  • Humans
  • Immunohistochemistry
  • Iron / metabolism*
  • Iron Regulatory Protein 2 / metabolism
  • Locomotion / genetics
  • Locomotion / physiology
  • Microscopy, Confocal
  • Nerve Tissue Proteins
  • Restless Legs Syndrome / genetics*
  • Restless Legs Syndrome / physiopathology*
  • Sleep Deprivation / genetics*
  • Sleep Deprivation / physiopathology
  • Transcription Factors / genetics


  • BTBD9 protein, Drosophila
  • BTBD9 protein, human
  • Carrier Proteins
  • Drosophila Proteins
  • Nerve Tissue Proteins
  • Transcription Factors
  • Iron
  • Iron Regulatory Protein 2
  • Dopamine