Reduced thiamine binding is a novel mechanism for TPK deficiency disorder
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Thiamine pyrophosphokinase (TPK) converts thiamine (vitamin B1) into thiamine pyrophosphate (TPP), an essential cofactor for many important enzymes. TPK1 mutations lead to a rare disorder: episodic encephalopathy type thiamine metabolism dysfunction. Yet, the molecular mechanism of the disease is not entirely clear. Here we report an individual case of episodic encephalopathy, with familial history carrying a novel homozygous TPK1 mutation (p.L28S). The L28S mutation leads to reduced enzymatic activity, both in vitro and in vivo, without impairing thiamine binding and protein stability. Thiamine supplementation averted encephalopathic episodes and restored the patient’s developmental progression. Biochemical characterization of reported TPK1 missense mutations suggested reduced thiamine binding as a new disease mechanism. Importantly, many disease mutants are directly or indirectly involved in thiamine binding. Thus, our study provided a novel rationale for thiamine supplementation, so far the major therapeutic intervention in TPK deficiency.
KeywordsNeurological disorder Thiamine metabolism TPK1 Disease mechanism and treatment
We thank our patients and their families and our coworkers. This research is supported by Natural Science Foundation of China (NSFC) grants (#80502629 to Q.S., and #31671477, #31871429, and #91854121 to D.J.), and Sichuan Science and Technology Program (2018RZ0128 to D.J.).
YMX and DJ conceived and supervised the project. WH, JQ, and DL performed biochemical work with assistance from YW, XS, NY and FX, YMX diagnosed the patient with assistance from HZ, XTC, ZLW, DY and RL, QS and DJ performed structural analysis. YMX and DJ prepared the manuscript. The authors declare no conflict of interest.
Compliance with ethical standards
Research involving human participants and/or animal rights
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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