Category: Rare Genetic and Metabolic Diseases
Objective: To identify new disease-gene in unsolved autosomal recessive primary familial brain calcifications.
Background: 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.
Method: We performed genome-wide sequencing, homozygosity mapping, segregation analysis and in-depth clinical and neuroimaging phenotyping for novel disease-causing gene discovery. We used immunofluorescence and fluorescence microscopy to assess subcellular distribution and characterization of disease variants as well as an in vitro carbon [14-C]-Nt-acetylation assay on immunoprecipitated variants to investigate their enzymatic activity. We used a zebra fish to model the disease and assess the phenotype. Pathogenicity was further confirmed by surface biotinylation assays and extracellular free phosphate quantification on patient-derived fibroblasts.
Results: Here, we identify biallelic NAA60 variants in seven individuals from four 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. A zebrafish disease model of NAA60 deficiency displayed a motor deficit with altered phosphate homeostasis.
Conclusion: This study establishes NAA60 as a causal gene for PFBC, provides a biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.
To cite this abstract in AMA style:V. Chelban, H. Aksnes, L. Lamonica, R. Maroofian, L. Seabra, P. Devic, J. Vandrovcova, D. Murphy, A. Pagnamenta, N. Wood, R. Horvath, A. Ernst, J. Rothman, M. Mcentagart, Y. Crow, G. Nicolas, T. Arnesen, H. Houlden. Impaired Nt-acetylation and the Golgi, a new disease mechanism leading to autosomal recessive primary familial brain calcifications [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/impaired-nt-acetylation-and-the-golgi-a-new-disease-mechanism-leading-to-autosomal-recessive-primary-familial-brain-calcifications/. Accessed September 25, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/impaired-nt-acetylation-and-the-golgi-a-new-disease-mechanism-leading-to-autosomal-recessive-primary-familial-brain-calcifications/