Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

原发性家族性脑钙化 （PFBC） 的特征是钙在大脑中沉积，导致进行性运动障碍、精神症状和认知能力下降。PFBC 是一种异质性疾病，目前与 6 个不同基因的变异有关，但大多数患者在基因上仍未确诊。在这里，我们在来自 7 个常染色体隐性遗传 PFBC 家族的 10 个个体中鉴定了双等位基因 NAA60 变异。NAA60 变体导致功能丧失，缺乏蛋白 N 末端 （Nt） 乙酰化活性。我们表明磷酸盐进口商 SLC20A2 是体外 NAA60 的底物。在细胞中，NAA60 的丢失导致 SLC20A2 表面水平降低和细胞外磷酸盐摄取减少。本研究将 NAA60 确定为 PFBC 的致病基因，为其致病机制提供了可能的生化解释，并强调了 NAA60 介导的跨膜蛋白 Nt 乙酰化是健康神经生物学功能的基本过程。