Department of Pediatrics, CHU Sainte-Justine, Montréal, Québec, Canada.
Research Centre, CHU Sainte-Justine, Montréal, Québec, Canada.
J Med Genet. 2024 Aug 29;61(9):886-890. doi: 10.1136/jmg-2024-109853.
Triokinase and FMN cyclase (TKFC) is a bifunctional enzyme involved in fructose metabolism. Triokinase catalyses the phosphorylation of fructose-derived glyceraldehyde (GA) and exogenous dihydroxyacetone (DHA), while FMN cyclase generates cyclic FMN. TKFC regulates the antiviral immune response by interacting with IFIH1 (MDA5). Previously reported pathogenic variants in are associated with either a multisystemic disease or isolated hypotrichosis with loose anagen hairs.
Whole-exome sequencing identified a homozygous novel variant in (c.1624G>A; p.Gly542Arg) in an individual with a complex primary immunodeficiency disorder. The variant was characterised using enzymatic assays and yeast studies of mutant recombinant proteins.
The individual presented with chronic active Epstein-Barr virus disease and multiple bacterial and viral infections. Clinical investigations revealed hypogammaglobulinaemia, near absent natural killer cells and decreased memory B cells. Enzymatic assays showed that this variant displayed defective DHA and GA kinase activity while maintaining FMN cyclase activity. An allogenic bone marrow transplantation corrected the patient's immunodeficiency.
Our report suggests that TKFC may have a role in the immunological system. The pathological features associated with this variant are possibly linked with DHA/GA kinase inactivation through a yet an unknown mechanism. This report thus adds a possible new pathway of immunometabolism to explore further.
三激酶和黄素单核苷酸环化酶（TKFC）是一种参与果糖代谢的双功能酶。三激酶催化果糖衍生的甘油醛（GA）和外源二羟丙酮（DHA）的磷酸化，而黄素单核苷酸环化酶生成环状 FMN。TKFC 通过与 IFIH1（MDA5）相互作用来调节抗病毒免疫反应。先前报道的 中的致病性变异与多系统疾病或孤立性少毛症伴疏松的生长期毛发有关。
全外显子组测序在一名患有复杂原发性免疫缺陷病的个体中发现了 中的一个纯合新型变异（c.1624G>A；p.Gly542Arg）。该变异通过酶促测定和突变重组蛋白的酵母研究进行了表征。
该个体表现为慢性活动性 EBV 病和多种细菌和病毒感染。临床研究发现低丙种球蛋白血症、几乎没有自然杀伤细胞和记忆 B 细胞减少。酶促测定显示该变异显示 DHA 和 GA 激酶活性缺陷，同时保持 FMN 环化酶活性。同种异体骨髓移植纠正了患者的免疫缺陷。
我们的报告表明 TKFC 可能在免疫系统中发挥作用。与该变异相关的病理特征可能与 DHA/GA 激酶失活有关，但其机制尚不清楚。因此，本报告增加了一个可能的新的免疫代谢途径，以进一步探索。
