Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 (GCH1) polymorphisms modulating pain and cardiovascular risk.

Journal article

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.

Authors: Doehring, A; Antoniades, C; Channon, K; Tegeder, I; Lötsch, J

• Publication status: Published
• Journal: Mutation research
• Volume: 659
• Issue: 3
• Pages: 195-201
• Publication date: 2008-01-01
• DOI: 10.1016/j.mrrev.2008.04.007
• EISSN: 1873-135X
• ISSN: 0027-5107
• Language: English
• Keywords: Pain; GTP Cyclohydrolase; Cardiovascular Diseases; Risk; Endothelium, Vascular; 3' Untranslated Regions; Heterozygote; Humans; Polymorphism, Single Nucleotide