Objective: Our ongoing study describes new NAA60-PBC cases, functionally characterizes additional NAA60 protein variants and investigates the cellular mechanisms underlying NAA60-PBC.

Background: NAA60 is a Golgi-localized N‑terminal (Nt) acetyltransferase modifying membrane proteins, whose physiological role has remained largely unresolved [1, 2]. Recently, biallelic pathogenic NAA60 variants were linked to primary brain calcification (PBC) [3], a hereditary neurodegenerative disorder characterized by bilateral calcium phosphate deposits in various brain regions. Affected individuals typically present with motoric, and/or psychiatric symptoms. NAA60 is the seventh PBC-associated gene, yet the underlying mechanisms driving calcification remain unknown and the number of NAA60-PBC cases are low. Our previous work described ten NAA60-PFBC cases from seven families [3] and in total only nine families and seven pathogenic NAA60 variants have been described [reviewed in 2].

Method: Pathogenic NAA60 protein variants were expressed and investigated for stability, subcellular localization and intrinsic Nt-acetyltransferase activity. Knockdown and knockout cell models were assessed for cellular PBC phenotypes: Golgi morphology by confocal fluorescence microscopy and transmission electron microscopy (TEM), and cellular uptake of inorganic phosphate (P_i) by P_i quantification kit.

Results: The missense variant retained Golgi localization but showed reduced enzymatic activity and protein stability. A novel NAA60 variant with truncation mutation lost Golgi localization and enzymatic activity and displayed severe protein instability. Immunofluorescence revealed Golgi fragmentation upon knockdown but less in the knockout, indicating a compensation mechanism. In-depth studies with TEM, point to another Golgi phenotype in NAA60 KO. P_i transport assay demonstrated impaired cellular P_i homeostasis in lysate from a NAA60 knockout model.

Conclusion: Our recent analyses strengthen the link between NAA60 and PBC with additional cases and demonstrate that PBC‑associated NAA60 variants impair protein stability, Golgi targeting, and/or enzymatic activity. These functional defects support a loss-of-function mechanism and highlight NAA60-mediated Nt-acetylation as a key player in cellular processes relevant to PBC, including Golgi integrity and P_i homeostasis.

References: 1. Aksnes et al. Cell Rep 2015. An organellar Nα-acetyltransferase, Naa60, acetylates cytosolic N termini of transmembrane proteins and maintains Golgi integrity. PMID: 25732826.
2. Siggervåg et al. Brain 2025. Understanding brain calcification via N-terminal acetylation at the Golgi apparatus. PMID: 40344186.
3. Chelban & Aksnes et al. Nat Commun 2024. Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications. PMID: 38480682.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/loss-of-naa60-mediated-n-terminal-acetylation-cause-primary-brain-calcification-with-disturbed-golgi-and-phosphate-maintenance-functions/