Reduced thiamine binding is a novel mechanism for TPK deficiency disorder

Thiamine pyrophosphokinase (TPK) converts thiamine (vitamin B-1) 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.

硫胺素焦磷酸激酶（TPK）将硫胺素（维生素B - 1）转化为硫胺素焦磷酸（TPP），TPP是许多重要酶的必需辅因子。TPK1突变导致一种罕见的疾病：发作性脑病型硫胺素代谢功能障碍。然而，该疾病的分子机制尚未完全明确。在此我们报道一例发作性脑病的个体病例，其家族史携带一种新的纯合TPK1突变（p.L28S）。L28S突变导致酶活性在体外和体内均降低，但不影响硫胺素结合和蛋白质稳定性。补充硫胺素避免了脑病发作，并恢复了患者的发育进程。对已报道的TPK1错义突变的生化特性研究表明，硫胺素结合减少是一种新的疾病机制。重要的是，许多疾病突变体直接或间接参与硫胺素结合。因此，我们的研究为补充硫胺素提供了一种新的理论依据，补充硫胺素是目前针对TPK缺乏的主要治疗干预措施。