A requirement for Gch1 and tetrahydrobiopterin in embryonic development

Abstract

IntroductionGTP cyclohydrolase I (GTPCH) catalyses the first and rate-limiting reaction in the synthesis of the enzymatic cofactor, tetrahydrobiopterin (BH4). Loss of function mutations in the GCH1 gene lead to congenital neurological diseases such as DOPA-responsive dystonia and hyperphenylalaninemia. However, little is known about how GTPCH and BH4 affects embryonic development in utero, and in particular whether metabolic replacement or supplementation in pregnancy is sufficient to rescue genetic GTPCH deficiency in the developing embryo.Methods and resultsGch1 deficient mice were generated by the insertion of loxP sites flanking exons 2–3 of the Gch1 gene. Gch1fl/fl mice were bred with Sox2cre mice to generate mice with global Gch1 deficiency. Genetic ablation of Gch1 caused embryonic lethality by E13.5. Despite loss of Gch1 mRNA and GTPCH enzymatic activity, whole embryo BH4 levels were maintained until E11.5, indicating sufficient maternal transfer of BH4 to reach this stage of development. After E11.5, Gch1−/− embryos were deficient in BH4, but an unbiased metabolomic screen indicated that the lethality was not due to a gross disturbance in metabolic profile. Embryonic lethality in Gch1−/− embryos was not caused by structural abnormalities, but was associated with significant bradycardia at E11.5. Embryonic lethality was not rescued by maternal supplementation of BH4, but was partially rescued, up to E15.5, by maternal supplementation of BH4 and l-DOPA.ConclusionThese findings demonstrate a requirement for Gch1 in embryonic development and have important implications for the understanding of pathogenesis and treatment of genetic BH4 deficiencies, as well as the identification of new potential roles for BH4.

Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway

“…These cause decreases in global BH4 levels below that required to maintain adequate NO and aromatic amine synthesis, as well as associated developmental defects (Bonafé et al, 2001; Douglas et al, 2015; Takazawa et al, 2008). The challenge then is how to reduce elevated BH4 in target tissues, such as sensory neurons and immune cells, without affecting excessively basal levels in the brain, endothelial cells, and liver.…”

Upregulation of AUF1 is involved in the proliferation of esophageal squamous cell carcinoma through GCH1

“…Among AUF1 affected genes, GCH1 encoded protein is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-dihydroneopterin triphosphate (25). BH4 is an essential element required for nitric oxide (No) formation by all nitric oxide synthases (NoSs) (26). No has been reported to modulate many cancer-related events, such as angiogenesis, apoptosis, cell cycle, invasion and metastasis (27), and correlated with the development of several cancers, including breast, cervical, lung, gastric and head and neck cancer (28)(29)(30)(31)(32)(33).…”

Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders

“…No association between changes of symptoms during the pregnancies and the type of drug treatment or the specific type of BH 4 deficiency was observed. Notably, the uncomplicated course of four pregnancies and good obstetrical outcome in two patients with adGTPCH-D despite not being on treatment suggests a milder disease course, which might be explained by reduced penetrance in adGTPCH-D (Thony and Blau 2006) and by high residual enzyme activity leading to sufficient catecholamine maintenance required for embryonic development (Opladen et al 2012, Douglas et al 2015.…”