Tetrahydrobiopterin (BH4) is an essential cofactor for the aromatic amino acid hydroxylases, alkylglycerol monooxygenase, and nitric oxide synthases (NOS). BH4 deficiency in humans is a heterogeneous group of rare disorders associated with a spectrum of phenotypes ranging from mild, peripheral symptoms including hyperphenylalaninemia (HPA) due to lowered hepatic PAH activity to severe morbidity due to compromised monoamine neurotransmitter synthesis by dysfunction of TH and TPH in the brain. Oral supplementation with BH4 — in combination with neurotransmitter precursors — has been successfully employed to treat patients.
It has previously been reported that homozygous knock-out mice for the 6-pyruvolytetrahydropterin synthase (PTPS; Pts-ko/ko) mice with no BH4 biosynthesis die after birth. In this study, Beat Thöny from University Children’s Hospital Zürich and her colleagues from the German Mouse Clinic comprehensively phenotyped a Pts-knock-in mouse model with a Pts-ki-allele expressing the murine PTPSp.Arg15Cys with low residual activity (15 % of wild-type in vitro).
The screening of Pts-ki/ki mice revealed alterations in energy metabolism with proportionally higher fat content but lower lean mass, and increased blood glucose and cholesterol. Transcriptome analysis indicated changes in glucose and lipid metabolism. Furthermore, differentially expressed genes associated with obesity, weight loss, hepatic steatosis, and insulin sensitivity were consistent with the observed phenotypic alterations. The scientists conclude that reduced PTPS activity concomitant with mildly compromised BH4-biosynthesis leads to abnormal body fat distribution and abdominal obesity at least in mice. This study associates a novel single gene mutation with monogenic forms of moderate obesity.
Germaine Korner, Tanja Scherer, Dea Adamsen, Alexander Rebuffat, Mark Crabtree, Anahita Rassi, Rossana Scavelli, Daigo Homma, Birgit Ledermann, Daniel Konrad, Hiroshi Ichinose, Christian Wolfrum, Marion Horsch, Birgit Rathkolb, Martin Klingenspor, Johannes Beckers, Eckhard Wolf, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Nenad Blau, Jan Rozman, Beat Thöny: Mildly compromised tetrahydrobiopterin cofactor biosynthesis due to Pts variants leads to unusual body fat distribution and abdominal obesity in mice. J Inherit Metab Dis (2016) 39:309–319. DOI 10.1007/s10545-015-9909-6