biostudies-literatureZhao MChinese Academy of Sciences (CAS)Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)China Postdoctoral Science FoundationNatural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)National Natural Science Foundation of China (National Science Foundation of China)128https://www.ebi.ac.uk/biostudies/studies/S-EPMC9705363biostudies-literatureUnknown8(1)Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy eCell discoveryLoss of function of CMPK2 causes mitochondria deficiency and brain calcification.PMC97053638190115831771139820250122019J02010ZR2019MH0608190132416JC1420202QYZDJ-SSW-SMC010821718412021J012212022M710704U1905210818708952021M693246Lin KJWang CLu YQCheng XLin BWZhao ZYZheng JWang NZhao MZhang YKGuo XXLin XHYao XPLai LLZuo DDLiu YBLin MTYang GZhao CPWang HTLi YLLiou CWZeng YHYang DSun YKong QXLi XYe ZLZuo EHuang XJLai THuang CWSu HZLuo WCen ZYan CZLin JXiong ZQChen WJHong SChen HZfalseLoss of function of CMPK2 causes mitochondria deficiency and brain calcification.Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy e2022-01-01T00:00:00Z2022 Nov2026-07-14T15:59:09.175Z2025-04-06T14:08:42.084ZS-EPMC97053633644331210.1038/s41421-022-00475-2