Abstract
Smith-Magenis syndrome (SMS), linked to Retinoic Acid Induced (RAI1) haploinsufficiency, is a unique model of the inversion of circadian melatonin secretion. In this regard, this model is a formidable approach to better understand circadian melatonin secretion cycle disorders and the role of the RAI1 gene in this cycle. Sleep-wake cycle disorders in SMS include sleep maintenance disorders with a phase advance and intense sleepiness around noon. These disorders have been linked to a general disturbance of sleep-wake rhythm and coexist with inverted secretion of melatonin. The exact mechanism underlying the inversion of circadian melatonin secretion in SMS has rarely been discussed. We suggest three hypotheses that could account for the inversion of circadian melatonin secretion and discuss them. First, inversion of the circadian melatonin secretion rhythm could be linked to alterations in light signal transduction. Second, this inversion could imply global misalignment of the circadian system. Third, the inversion is not linked to a global circadian clock shift but rather to a specific impairment in the melatonin secretion pathway between the suprachiasmatic nuclei (SCN) and pinealocytes. The development of diurnal SMS animal models that produce melatonin appears to be an indispensable step to further understand the molecular basis of the circadian melatonin secretion rhythm.
Highlights
The study of the phenotype linked to a single genetic event is an excellent way to improve our knowledge regarding common health issues
We suggest that three hypotheses could account for an inversion of the circadian melatonin secretion rhythm in Smith-Magenis syndrome (SMS) patients
We hypothesize that the inversion of the circadian melatonin secretion rhythm reflects a phenomenon located downstream of the circadian trigger of the suprachiasmatic nuclei (SCN)
Summary
The study of the phenotype linked to a single genetic event is an excellent way to improve our knowledge regarding common health issues. Smith-Magenis syndrome (SMS) is a formidable approach to better understand circadian melatonin secretion cycle disorders and the role of the Retinoic Acid Induced (RAI1) gene in this cycle. In 90% of cases, SMS is linked to a microdeletion of chromosome 17 (Figure 1) that encompasses the RAI1 gene and causes major sleep-wake disorders [1,2,3,4]. SMS is caused by a heterozygous mutation in the RAI1 gene. The main clinical features of SMS include intellectual disability, dysmorphism and characteristic disturbances of the sleep-wake rhythm. SMS is a unique model of inversion of the circadian melatonin secretion cycle. 2019, 20, x FOR PEER REVIEW recent development of animal models, murine models, should make it possible to further and the recent of animal models, murine models, should make it possible understand thedevelopment physiopathology of this inversion.
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