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Neurogastroenterol Motil. 2015 Jul;27(7):990-6. doi: 10.1111/nmo.12575. Epub 2015 Apr 29.

NextGen nuclear DNA sequencing in cyclic vomiting syndrome reveals a significant association with the stress-induced calcium channel (RYR2).

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Courtagen Life Sciences Inc., Woburn, MA, USA.
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Division of Medical Genetics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Department of Pediatrics, Keck School of Medicine at USC, Los Angeles, CA, USA.



Cyclic vomiting syndrome (CVS) is a common, frequently disabling, 'functional' condition characterized by recurring, stereotypical attacks of intense nausea, vomiting, and lethargy, with the essential absence of these symptoms between episodes. Although the pathogenesis of CVS is yet unexplained, evidence has accumulated which suggest pathogenic roles for stress-related, autonomic, neuroendocrine, and mitochondrial factors. The objective of this pilot study was to elucidate mechanism(s) by identifying genes involved in the presumed multifactorial pathogenesis of CVS.


In this pilot study, DNA from 75 unrelated CVS cases and 60 healthy controls were assayed by Courtagen Life Science's next-generation sequencing platform (nucSEEK(™) ), including over 1100 nuclear-encoded genes involved with mitochondria, metabolism, or ion channels. Significant sequence variants were defined as evolutionary conservation at least to Xenopus (frog) per the UCSC Genome Browser.


The RYR2 gene, encoding a stress-induced calcium channel present in many neurons, was the only gene demonstrating a statistically significant difference in the proportion of conserved sequence variants among the groups (18/75 CVS, 24%, vs 3/60 controls, 5%; p = 0.0018, OR = 6.0, 95% CI = 1.7-22).


We propose a mechanism in which RYR2 sequence variants result in aberrant stress-induced calcium release into the mitochondria of autonomic neurons, resulting in an increased risk to develop autonomic/functional disease such as CVS, and related conditions such as migraine and gut dysmotility. This model incorporates the existing hypotheses regarding CVS pathogenesis into a cohesive mechanism, and might have treatment implications.


CVS; LETM1; Mitochondria; PNKD; POLG; Ryanodine; TRAP1

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