The evolutionarily conserved mevalonate pathway plays an important role in the synthesis of cholesterol and isoprenoid compounds. Mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) enzymes regulate key rate-limiting steps in this pathway by sequentially phosphorylating mevalonic acid to yield downstream metabolites that regulate protein prenylation and cell signaling. Biallelic pathogenic variants in MVK cause a spectrum of rare autoinflammatory disorders that encompass milder forms of hyper-IgD syndrome (HIDS) at one end and the more severe mevalonic aciduria on the other. In contrast, pathogenic variants reported in PMVK are heterozygous and associated with porokeratosis, a skin disorder with no systemic manifestations. Recently, biallelic variants in PMVK were reported as a cause for an autoinflammatory disorder for the first time in two unrelated patients. In this study, we describe a child with recurrent arthritis and a HIDS-like phenotype harboring a novel homozygous variant c.398 C>T (p.Ala133Val) in PMVK. Mononuclear cells isolated from the patient showed significantly elevated production of interleukin 1β, a key cytokine that shapes the inflammatory response in HIDS. Protein modeling studies suggested potential defects in PMVK enzyme activity. These results posit a further expanding of the genotypic spectrum of autoinflammatory disease to include biallelic PMVK variants.

中文翻译：

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PMVK 中的一种新型纯合变异与 IL1β 分泌增强和高 IgD 综合征样表型相关

进化上保守的甲羟戊酸途径在胆固醇和类异戊二烯化合物的合成中发挥着重要作用。甲羟戊酸激酶 ( MVK ) 和磷酸甲羟戊酸激酶 ( PMVK ) 通过依次磷酸化甲羟戊酸产生调节蛋白质异戊二烯化和细胞信号传导的下游代谢物，调节该途径中的关键限速步骤。MVK中的双等位基因致病变异会导致一系列罕见的自身炎症性疾病，其中一端包括较温和的高 IgD 综合征 (HIDS)，另一端包括更严重的甲羟戊酸尿症。相比之下，PMVK中报告的致病变异是杂合的，并与汗孔角化症（一种没有全身表现的皮肤病）相关。最近，PMVK的双等位基因变异首次被报道为两名无关患者的自身炎症性疾病的原因。在这项研究中，我们描述了一名患有复发性关节炎和 HIDS 样表型的儿童，该儿童在 PMVK 中含有新型纯合变异 c.398 C>T (p.Ala133Val) 。从患者体内分离出的单核细胞显示白细胞介素 1β 的产生显着升高，白细胞介素 1β 是一种影响 HIDS 炎症反应的关键细胞因子。蛋白质模型研究表明 PMVK 酶活性存在潜在缺陷。这些结果表明自身炎症性疾病的基因型谱进一步扩大，包括双等位基因PMVK变体。