Journal
MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH
Volume 659, Issue 3, Pages 195-201Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrrev.2008.04.007
Keywords
GCH1; tetrahydrobiopterin; single nucleotide polymorphism
Funding
- NINDS NIH HHS [NS058870] Funding Source: Medline
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Guanosine triphosphate cyclohydrolase 1 (GCH 1) 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 GCH 1 gene, leading mostly to a dominant negative enzyme. However, recent evidence suggests a clinical genetics of GCH 1 beyound these hereditary loss-of-function diseases. That is, a non-coding GCH 1 haplotype has been associated with reduced pain hypersensitivity and with altered vascular endothelial function. Moreover, the presence of the noncoding c 243>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 GCH 1 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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