Alternative titles; symbols
HGNC Approved Gene Symbol: NAA60
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:3,443,611-3,486,963 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Basal ganglia calcification, idiopathic, 9, autosomal recessive | 620786 | Autosomal recessive | 3 |
N-terminal acetylation is a common protein modification that occurs cotranslationally and may be necessary to regulate protein function, localization, and/or stability. NAA60 is an N-acetyltransferase (NAT) that has broad substrate specificity and can acetylate N-terminal methionines (Van Damme et al., 2011).
By searching databases for sequences similar to NATs, Van Damme et al. (2011) identified NAA60. The deduced 242-amino acid protein is similar to other NATs predominantly in its N-terminal half, which includes an acyl-CoA-binding motif. Database analysis revealed conservation of NAA60 among animals and, potentially, higher plants, but not lower organisms.
Hartz (2011) mapped the NAA60 gene to chromosome 16p13.3 based on an alignment of the NAA60 sequence (GenBank AK024216) with the genomic sequence (GRCh37).
By assaying the activity of recombinant NAA60 expressed in E. coli, Van Damme et al. (2011) showed that NAA60 alpha-acetylated numerous peptides in vitro and displayed a distinct substrate specificity profile. The preferred N termini included met-lys, met-ala, met-val, and met-met. Expression of human NAA60 significantly elevated total protein acetylation and altered the profile of protein acetylation in yeast, which do not express an ortholog of NAA60. Overexpression or knockdown of NAA60 in HeLa cells increased or decreased N-terminal protein acetylation, respectively. Knockdown of Naa60 in Drosophila Dmel2 cells caused a chromosome segregation defect that was independent of abnormalities in kinetochore, cohesion, centrosome, mitotic spindle, and actin and microtubule cytoskeleton.
Genomic imprinting is an epigenetic process mediated by DNA methylation and repressive histone modifications in which 1 allele is repressed, resulting in parent-of-origin specific monoallelic expression. Using reciprocal genomewide uniparental disomy samples identified with Beckwith-Wiedemann syndrome (BWS; 130650)- and Silver-Russell syndrome (SRS; 180860)-like phenotypes, Nakabayashi et al. (2011) analyzed CpG dinucleotides present in the human genome for imprinted differentially methylated regions (DMRs) by methylation beadchip microarray analysis. In addition to 15 imprinted DMRs associated with characterized imprinted domains, Nakabayashi et al. (2011) identified 2 novel DMRs: a maternally methylated region overlapping the FAM50B (614686) promoter CpG island, resulting in paternal expression of this retrotransposon, and a paternally methylated bidirectional repressor located between the maternally expressed ZNF597 (614685) and NAT15 genes. In mice, all 3 genes have unmethylated CpG islands and are biallelically expressed. Nakabayashi et al. (2011) proposed that FAM50B, ZNF597, and NAT15 became imprinted after the divergence of mice and humans.
In 10 patients from 7 families, including 3 sib pairs, with idiopathic basal ganglia calcification-9 (IBGC9; 620786), Chelban et al. (2024) identified homozygous mutations in the NAA60 gene (614246.0001-614246.0006). Constructs with each individual mutation in NAA60 were expressed in RPE-1 cells. NAA60 with the c.321_327del (614246.0001) and c.338-1G-C (614246.0002) mutations had abnormal cytosolic and nuclear localization, whereas NAA60 with the other mutations had intact subcellular localization. Chelban et al. (2024) found that NAA60 had N-alpha-acetyltransferase capabilities and that SLC20A2 (158378) and MYORG (618255) were both N-terminal-acetylation substrates of NAA60. SLC20A2 cell surface expression was reduced in fibroblasts from the sibs in family 1. Given the role of SLC20A2 in inorganic phosphate transport, Chelban et al. (2024) tested the ability of fibroblasts from these sibs to uptake inorganic phosphate and found that it was reduced compared to wildtype. Chelban et al. (2024) concluded that IBGC9 is caused by mutations in NAA60 due to impaired cellular inorganic phosphate homeostasis, possibly by abnormal N-terminal-acetylation of SLC20A2.
In 2 sibs, born of nonconsanguineous parents (family 1), with idiopathic basal ganglia calcification-9 (IBGC9; 620786), Chelban et al. (2024) identified homozygosity for a 7-bp deletion (c.321_327del, NM_001083601) in the NAA60 gene, predicted to result in a frameshift and premature termination (Arg108ThrfsTer3). The mutation, which was identified by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was present twice in the gnomAD database (v2.1) in only heterozygous state and was present in the 100K Genome Project database at an allele frequency of 1/156390.
In 2 Algerian sibs, born to consanguineous parents (family 2), and 2 Moroccan sibs, born to consanguineous parents (family 3), with idiopathic basal ganglia calcification-9 (IBGC9; 620786), Chelban et al. (2024) identified homozygosity for a c.338-1G-C transversion (c.338-1G-C, NM_001083601) in the NAA60 gene, predicting deletion of 20 nucleotides and resulting in a frameshift and premature termination (Gly113ValfsTer32). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in both sets of parents. The authors found no close relatedness or shared haplotpe blocks surrounding NAA60 between the families, suggesting that this was a recurrent mutation. The variant was not present in the gnomAD (v2.1) and 100K Genome Project databases.
In a Gujarati patient, born to nonconsanguineous parents (family 4), with idiopathic basal ganglia calcification-9 (IBGC9; 620786), Chelban et al. (2024) identified homozygosity for a c.391C-T transition (c.391C-T, NM_001083601) in the NAA60 gene, resulting in a his131-to-tyr (H131Y) substitution. The mutation, which was identified by whole-genome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was present in the gnomAD database (v2.1) in only heterozygous state at an allele frequency of 3/152156 and was present in the 100K Genome Project database at an allele frequency of 5/156390.
In a patient, born to consanguineous parents (family 5), with idiopathic basal ganglia calcification-9 (IBGC9; 620786), Chelban et al. (2024) identified homozygosity for a c.130C-T transition (c.130C-T, NM_001083601) in the NAA60 gene, resulting in an arg44-to-cys (R44C) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was not present in the gnomAD (v2.1) and 100K Genome Project databases.
In a Turkish patient, born to consanguineous parents (family 6), with idiopathic basal ganglia calcification-9 (IBGC9; 620786), Chelban et al. (2024) identified homozygosity for a c.50T-G transversion in the NAA60 gene, resulting in a leu17-to-arg (L17R) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was present in the gnomAD database (v2.1) in heterozygous state at an allele frequency of 1/17976 and was absent in the 100K Genome Project database.
In a Saudi patient, born to nonconsanguineous parents (family 7), with idiopathic basal ganglia calcification-9 (IBGC9; 620786), Chelban et al. (2024) identified homozygosity for a c.428A-C transversion in the NAA60 gene, resulting in an asn143-to-thr (N143T) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was present in the gnomAD database (v2.1) in only heterozygous state at an allele frequency of 2/249122 and was absent in the 100K Genome Project database. NAA60 protein expression was reduced in primary dermal fibroblasts from the patient compared to wildtype.
Chelban, V., Aksnes, H., Maroofian, R., LaMonica, L. C., Seabra, L., Siggervag, A., Devic, P., Shamseldin, H. E., Vandrovcova, J., Murphy, D., Richard, A. C., Quenez, O., and 48 others. Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications. Nature Commun. 15: 2269, 2024. [PubMed: 38480682] [Full Text: https://doi.org/10.1038/s41467-024-46354-0]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/22/2011.
Nakabayashi, K., Trujillo, A. M., Tayama, C., Camprubi, C., Yoshida, W., Lapunzina, P., Sanchez, A., Soejima, H., Aburatani, H., Nagae, G., Ogata, T., Hata, K., Monk, D. Methylation screening of reciprocal genome-wide UDPs identifies novel human-specific imprinted genes. Hum. Molec. Genet. 20: 3188-3197, 2011. [PubMed: 21593219] [Full Text: https://doi.org/10.1093/hmg/ddr224]
Van Damme, P., Hole, K., Pimenta-Marques, A., Helsens, K., Vandekerckhove, J., Martinho, R. G., Gevaert, K., Arnesen, T. NatF contributes to an evolutionary shift in protein N-terminal acetylation and is important for normal chromosome segregation. PLoS Genet. 7: e1002169, 2011. Note: Electronic Article. [PubMed: 21750686] [Full Text: https://doi.org/10.1371/journal.pgen.1002169]