An epigenetic mechanism identified in POTS (Postural tachy syndrome)

[ramakentesh]

http://atvb.ahajournals.org/content/early/2012/06/21/ATVBAHA.111.244343.abstract:

Objective—The postural tachycardia syndrome (POTS) has multiple symptoms, chief among which are tachycardia, weakness, and recurrent blackouts while standing. Previous research has implicated dysfunction of the norepinephrine transporter. A coding mutation in the norepinephrine transporter gene (SLC6A2) sequence has been reported in 1 family kindred only. The goal of the present study was to further characterize the role and regulation of the SLC6A2 gene in POTS.
Methods and Results—Sympathetic nervous system responses to head-up tilt were examined by combining norepinephrine plasma kinetics measurements and muscle sympathetic nerve activity recordings in patients with POTS compared with that in controls. The SLC6A2 gene sequence was investigated in leukocytes from POTS patients and healthy controls using single nucleotide polymorphisms genotyping, bisulphite sequencing, and chromatin immunoprecipitation assays for histone modifications and binding of the transcriptional regulatory complex, methyl-CpG binding protein 2. The expression of norepinephrine transporter was lower in POTS patients compared with healthy volunteers. In the absence of altered SLC6A2 gene sequence or promoter methylation, this reduced expression was directly correlated with chromatin modifications.
Conclusion—We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS

 

[ramakentesh]

To explain this mechanism in laymans terms (using the findings of the NET deficiency proband), reduced NET expression leads to a phenotype of increased peripheral alpha transduction and resting peripheral vasoconstriction, leading to reduced stroke volume and compenstory parasympathetic withdrawal. However reduced NET in the CNS results in reduced CNS sympathetic activity. NET may also effect peripheral dopamine levels resulting in upright salt extraction from the kidneys and effect volume status.
End result is often postural hypertension (but not always), occasionally increased MSNA and abnormal cerebral autoregulation causing increased cerebral vasoconstriction on upright positions.

 

[adreno]

Thanks for posting. Did you read the full text? Do they list the SNPs involved?

 

[ramakentesh]

yes I did and its highly complex. basically histone modifying subtances appear to be attaching markers to the promoter of the NET gene but these are not traditional hypermethylating promoter CpG island cloggers, rather this is something new. They have not yet determined the cause of the imbalance in transcriptional regulating substances but suggest that it may be driven by Cytokines - as my other post refers to.