Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 (GCH1) polymorphisms modulating pain and cardiovascular risk.
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| Abstract |
Guanosine triphosphate cyclohydrolase 1 (GCH1) is the first enzyme in the tetrahydrobiopterin (BH4) biosynthesis, an important co-factor for the formation of nitric oxide, biogenic amines and serotonin. Hereditary diseases such as DOPA-responsive dystonia and atypical phenylketonuria are known to be caused by coding or splice-site mutations in the GCH1 gene, leading mostly to a dominant negative enzyme. However, recent evidence suggests a clinical genetics of GCH1 beyond these hereditary loss-of-function diseases. That is, a non-coding GCH1 haplotype has been associated with reduced pain hypersensitivity and with altered vascular endothelial function. Moreover, the presence of the non-coding c.*243C>T variant in the 3'-untranslated region (3'-UTR) of the GCH1 gene has been associated with mildly increased heart rate and blood pressure. Here, we show that carriers of the pain-protective GCH1 haplotype also carry the c.*243C>T variant and vice versa. We thus demonstrate that apart from the coding or splice-site variants causing DOPA-responsive dystonia and atypical phenylketonuria, there is a common clinically relevant GCH1 genetics that is so far known to be related to unfavorable changes of endothelial function and a reduced risk for chronic pain.
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| Authors | Alexandra Doehring, Charalambos Antoniades, Keith M Channon, Irmgard Tegeder, Jörn Lötsch |
| Journal | Mutation research (Mutat Res) 2008 Sep-Oct Vol. 659 Issue 3 Pg. 195-201 ISSN: 0027-5107 [Print] Netherlands |
| PMID | 18515178 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review) |
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