Alternative titles; symbols
HGNC Approved Gene Symbol: NAA15
Cytogenetic location: 4q31.1 Genomic coordinates (GRCh38) : 4:139,301,505-139,391,384 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q31.1 | Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities | 617787 | Autosomal dominant | 3 |
The NAA15 gene encodes a component of the NatA N-acetyltransferase complex that is thought to tether the complex to the ribosome for posttranslational modification of proteins as they exit the ribosome (summary by Stessman et al., 2017).
By replica cDNA screening for genes upregulated in papillary thyroid carcinomas, Fluge et al. (2002) cloned NARG1 (NAA15), which they called NATH. The deduced 866-amino acid protein has a calculated molecular mass of 101 kD. It contains 4 tetratricopeptide repeat domains in 2 tandems and a putative bipartite nuclear localization signal. NATH shares similarity with S. cerevisiae N-acetyltransferase-1 (NAT1; 108345) and mouse Narg1 and Tbdn1. Northern blot analysis detected a major transcript of 4.6 kb and a minor transcript of 5.8 kb in a papillary carcinoma cell line and in an anaplastic thyroid carcinoma cell line. Multitissue mRNA dot blot analysis showed low expression in most adult tissues and specific brain regions examined. Highest expression was detected in testis and a Burkitt lymphoma cell line. Expression of NATH in COS-7 cells resulted in cytoplasmic staining.
By Northern blot analysis, Sugiura et al. (2001) found that expression of mouse Narg1 was highest in testis and much lower in other tissues examined. They cloned 2 alternatively spliced variants of mouse Narg1 from testis. The deduced proteins contained 865 and 815 amino acids. The shorter protein has an N-terminal truncation.
By analyzing cDNA arrays, Sugiura et al. (2001) found the expression of Narg1, Narg2 (610835), and Narg3 was upregulated in neonatal mice in which the gene for the Nmda receptor (NMDAR1; GRIN1 138249) was deleted. In situ hybridization of wildtype neonatal mouse brain showed that Narg1, Narg2, and Narg3 were expressed at high levels in regions of neuronal proliferation and migration, and their expression was downregulated during early postnatal development. Northern blot analysis detected low expression of these genes on embryonic day 13, high expression on postnatal day 0, and very low expression thereafter.
By semiquantitative RT-PCR, Fluge et al. (2002) found NATH overexpressed in papillary thyroid carcinomas, especially in clinically aggressive tumors with histologic evidence of poorly differentiated or undifferentiated areas. In situ hybridization detected NATH highly expressed in tumor cells and only weakly expressed in adjacent nonneoplastic thyroid follicular cells. Transfection of NATH into a papillary carcinoma cell line or embryonic kidney cells did not alter the cellular proliferation rate.
Using in vitro translated mouse proteins, Sugiura et al. (2003) showed that Narg1 and Ard1 (ARD1A, NAA10; 300013) assembled to form a functional acetyltransferase. Narg1 alone showed no activity. Immunoprecipitation and Western blot analysis demonstrated that Narg1 and Ard1 coassembled in mammalian cells. By cotransfection of rat kidney fibroblasts, they showed that Narg1 and Ard1 localized to the cytoplasm in both overlapping and separate compartments. In situ hybridization demonstrated that throughout mouse brain development Narg1 and Ard1 were highly expressed in areas of cell division and migration and their expression appeared to be downregulated as neurons differentiated. Narg1 and Ard1 were expressed in proliferation mouse embryonic carcinoma cells. Treatment of these cells with retinoic acid initiated neuronal differentiation and downregulation of Narg1 and Ard1 as a neuronal marker gene was induced. Sugiura et al. (2003) concluded that NARG1 and ARD1 plays a role in the generation and differentiation of neurons.
Asaumi et al. (2005) confirmed interaction of APP (104760) with ARD1A in mammalian cells by coimmunoprecipitation studies. Using human ACTH as a substrate, they showed that the ARD1/NARG1 complex has strong N-terminal transferase activity. Immunoprecipitation and Western blotting experiments showed that ARD1 and NARG1 formed a complex in HEK293 cells. Because APP-binding proteins can modulate APP metabolism, they tested the ability of ARD1 to modulate beta-amyloid-40 secretion and found that coexpression of both ARD1 and NARG1 was required to suppress beta-amyloid-40 generation from APP. APP endocytosis assay in HEK293 cells showed that ARD1 and NARG1 suppressed endocytosis of APP.
Using reciprocal immunoprecipitation followed by mass spectroscopic analysis, Arnesen et al. (2005) showed that endogenous ARD1 and NATH formed stable complexes in several human cell lines and that the complex showed N-terminal acetylation activity. Mutation analysis and examination of proteolytic fragments indicated that the interaction was mediated through an N-terminal domain of ARD1 and the C-terminal end of NATH. Immunoprecipitation analysis showed ARD1 and NATH associated with several ribosomal proteins. ARD1 and NATH were also detected in isolated polysomes; however, they were predominantly nonpolysomal. Endogenous ARD1 was present in both the nuclei and cytoplasm in several human cell lines, whereas NATH was predominantly in the cytoplasm, despite the presence of a well-defined nuclear localization signal within the NATH coiled-coil region. Both ARD1 and NATH were cleaved in a caspase-dependent manner during apoptosis in stressed HeLa cells, resulting in reduced acetylation activity.
Fluge et al. (2002) determined that the NARG1 gene contains at least 24 exons and spans 90 kb.
By genomic sequence analysis, Fluge et al. (2002) mapped the NARG1 gene to chromosome 4.
Stumpf (2021) mapped the NAA15 gene to chromosome 4q31.1 based on an alignment of the NAA15 sequence (GenBank AF327722) with the genomic sequence (GRCh38).
Sugiura et al. (2001) referred to NARG1 as mNat1 due to its homology with yeast Nat1; this creates confusion with the NAT1 gene (108345).
In 13 unrelated patients with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Stessman et al. (2017) identified 13 different heterozygous variants in the NAA15 gene (see, e.g., 608000.0001-608000.0003). Ten of the variants were categorized as 'likely gene disruptive' (LGD) events, such as nonsense or frameshift variants, and 3 were missense variants predicted to be deleterious. Four of the variants, all of which were LGD, were demonstrated to have occurred de novo. One missense variant was paternally inherited without clinical information on the father, and parental DNA was not available for the other 8 patients to determine segregation. Ten of the variants were private (family) and identified only in the affected patient; 3 were classified as 'ultra-rare.' Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a large cohort of over 11,730 patients with autism spectrum disorder, intellectual disability, and/or developmental delay involving 15 centers across 7 countries and 4 continents. The authors used single-molecule molecular inversion probes (smMIPs) to sequence 208 candidate genes in these patient samples. The findings of de novo LGD mutations in the NAA15 gene was statistically significant. Using statistical analysis, Stessman et al. (2017) stated that given the incidence of developmental delay in the general population (5.12%), the penetrance of LGD NAA15 mutations was estimated to be 35.3%.
In 39 patients from 34 unrelated families with MRD50, including the patients previously reported by Stessman et al. (2017), Cheng et al. (2018) identified 25 heterozygous variants in the NAA15 gene (see, e.g., 608000.0004-608000.0007). Most of the mutations occurred de novo, although 3 families showed autosomal dominant inheritance of the mutations. All of the mutations were classified as LGD, including nonsense, frameshift, and splice site mutations. The mutations occurred throughout the gene and were predicted or demonstrated to result in nonsense-mediated mRNA decay and a loss of protein function in cells derived from some of the patients. Expression of several of the mutations in NatA-null yeast failed to rescue growth defects, indicating that they caused a loss of function. Cheng et al. (2018) concluded that haploinsufficiency of NAA15 was the most likely mechanism for this variable neurodevelopmental disorder, although the possibility of a dominant-negative or gain-of-function mechanism could not be excluded.
In 7 unrelated patients with MRD50, including 3 previously reported by Stessman et al. (2017), Cheng et al. (2019) identified 7 different heterozygous missense variants in the NAA15 gene (see, e.g., 608000.0008-608000.0010). The variants, which were found by exome sequencing, were either absent from gnomAD or present at a low frequency in that database. Four of the mutations were proven to be de novo, 2 were inherited from either unaffected or mildly affected parents, and the inheritance pattern was unknown for the remaining patient. In vitro functional expression studies showed variable effects of the variants: some resulted in decreased or increased enzymatic activity, whereas some stabilized or destabilized the NatA complex. However, most variants produced no significant decrease in activity of the NatA complex. Studies of patient cells were not performed. These findings suggested that the phenotypic variability resulted from different biochemical effects of the variants. The 2 inherited variants were found in the gnomAD database, thus limiting the support for pathogenicity.
In a 6-year-old boy (patient 7, Antwerp_105005) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Stessman et al. (2017) identified a de novo heterozygous c.1695T-A transversion (c.1695T-A, NM_057175.3) in the NAA15 gene, resulting in a tyr565-to-ter (Y565X) substitution. The mutation was found by candidate gene sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. The patient had global developmental delay, delayed speech, aggressive behavior, autistic features, and nonspecific dysmorphic features.
In a 31-year-old man (patient 9, Antwerp_106663) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Stessman et al. (2017) identified a de novo heterozygous c.2086A-T transversion (c.2086A-T, NM_057175.3) in the NAA15 gene, resulting in a lys696-to-ter (K696X) substitution. The mutation was found by candidate gene sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. The patient had intellectual disability and autism spectrum disorder.
In a male patient (patient 11, AGRE_03C14733) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787) manifest as autism spectrum disorder, Stessman et al. (2017) identified a de novo heterozygous del/ins mutation (c.225_230delTGACTTinsT, NM_057175.3) in the NAA15 gene, resulting in a frameshift and premature termination (Asp76GlufsTer20).
In a mother and her 2 sons (family 10) and in 6 additional unrelated patients with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Cheng et al. (2018) identified a heterozygous 2-bp deletion (c.239_240delAT, NM_057175.4) in exon 3 of the NAA15 gene, predicted to result in a frameshift and premature termination (His80ArgfsTer17). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was found once in the ExAC database. RT-PCR analysis of patient cells showed reduced mutant mRNA levels, consistent with nonsense-mediated mRNA decay and a loss of function. One of the patients (individual 8) had previously been reported as subject 2 in Stessman et al. (2017).
In a 17-year-old boy (family 2) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Cheng et al. (2018) identified a de novo heterozygous 1-bp deletion (c.163delA, NM_057175.4) in exon 3 of the NAA15 gene, predicted to result in a frameshift and premature termination (Thr55HisfsTer2). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Expression of the mutation into NatA-null yeast failed to rescue the growth phenotype, suggesting that it results in a loss of function. Mutant NAA15 mRNA could not be detected by immunoblot analysis, consistent with nonsense-mediated mRNA decay.
In an 8-year-old boy (patient 19) and an unrelated 12-year-old girl (patient 20) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Cheng et al. (2018) identified a de novo heterozygous 4-bp deletion (c.1009_1012delGAAA, NM_057175.4) in exon 9 of the NAA15 gene, resulting in a frameshift and premature termination (Glu337ArgfsTer5). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of patient cells showed almost complete absence of the mutant NAA15 mRNA, suggesting nonsense-mediated mRNA decay and a loss of function.
In a 10-year-old girl (patient 18) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Cheng et al. (2018) identified a de novo heterozygous c.913A-T transversion (c.913A-T, NM_057175.4) in exon 9 of the NAA15 gene, resulting in a lys305-to-ter (K305X) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Expression of the mutation into NatA-null yeast failed to rescue the growth defect, suggesting a loss of function.
In a 17-year-old boy (patient 1) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Cheng et al. (2019) identified a heterozygous c.334G-A transition (c.334G-A, NM_057175.3) in exon 4 of the NAA15 gene, resulting in an asp112-to-asn (D112N) substitution. The patient had been reported as patient 12 by Stessman et al. (2017). The variant, which was found by exome sequencing, was not present in the gnomAD database. The inheritance pattern was unknown. In vitro functional expression studies showed that the D112N variant had no effect on enzymatic activity, but caused increased stabilization of the NatA complex compared to wildtype NAA15. The patient had Asperger syndrome.
In a 6-year-old girl (patient 6) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Cheng et al. (2019) identified a de novo heterozygous c.1450T-C transition (c.1450T-C, NM_057175.3) in exon 6 of the NAA15 gene, resulting in a cys484-to-arg (C484R) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the mutation resulted in decreased enzyme activity compared to wildtype and destabilized the NatA complex. The patient also carried a de novo heterozygous missense variant (R613C) in the TCF12 gene (600480) that was possibly pathogenic.
In an 8-year-old girl (patient 7) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787), Cheng et al. (2019) identified a de novo heterozygous c.2441T-C transition (c.2441T-C, NM_057175.3) in exon 20 of the NAA15 gene, resulting in a leu814-to-pro (L814P) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the variant increased enzymatic activity compared to wildtype under certain conditions; it also destabilized the NatA complex.
Arnesen, T., Anderson, D., Baldersheim, C., Lanotte, M., Varhaug, J. E., Lillehaug, J. R. Identification and characterization of the human ARD1-NATH protein acetyltransferase complex. Biochem. J. 386: 433-443, 2005. [PubMed: 15496142] [Full Text: https://doi.org/10.1042/BJ20041071]
Asaumi, M., Iijima, K., Sumioka, A., Iijima-Ando, K., Kirino, Y., Nakaya, T., Suzuki, T. Interaction of N-terminal acetyltransferase with the cytoplasmic domain of beta-amyloid precursor protein and its effect on A-beta secretion. J. Biochem. 137: 147-155, 2005. [PubMed: 15749829] [Full Text: https://doi.org/10.1093/jb/mvi014]
Cheng, H., Dharmadhikari, A. V., Varland, S., Ma, N., Domingo, D., Kleyner, R., Rope, A. F., Yoon, M., Stray-Pedersen, A., Posey, J. E., Crews, S. R., Eldomery, M. K., and 60 others. Truncating variants in NAA15 are associated with variable levels of intellectual disability, autism spectrum disorder, and congenital anomalies. Am. J. Hum. Genet. 102: 985-994, 2018. [PubMed: 29656860] [Full Text: https://doi.org/10.1016/j.ajhg.2018.03.004]
Cheng, H., Gottlieb, L., Marchi, E., Kleyner, R., Bhardwaj, P., Rope, A. F., Rosenheck, S., Moutton, S., Philippe, C., Eyaid, W., Alkuraya, F. S., Toribio, J., and 17 others. Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15. Hum. Molec. Genet. 28: 2900-2919, 2019. Note: Erratum: Hum. Molec. Genet. 29: 877-878, 2020. [PubMed: 31127942] [Full Text: https://doi.org/10.1093/hmg/ddz111]
Fluge, O., Bruland, O., Akslen, L. A., Varhaug, J. E., Lillehaug, J. R. NATH, a novel gene overexpressed in papillary thyroid carcinomas. Oncogene 21: 5056-5068, 2002. [PubMed: 12140756] [Full Text: https://doi.org/10.1038/sj.onc.1205687]
Stessman, H. A. F., Xiong, B., Coe, B. P., Wang, T., Hoekzema, K., Fenckova, M., Kvarnung, M., Gerdts, J., Trinh, S., Cosemans, N., Vives, L., Lin, J., and 41 others. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nature Genet. 49: 515-526, 2017. [PubMed: 28191889] [Full Text: https://doi.org/10.1038/ng.3792]
Stumpf, A. M. Personal Communication. Baltimore, Md. 07/06/2021.
Sugiura, N., Adams, S. M., Corriveau, R. A. An evolutionarily conserved N-terminal acetyltransferase complex associated with neuronal development. J. Biol. Chem. 278: 40113-40120, 2003. [PubMed: 12888564] [Full Text: https://doi.org/10.1074/jbc.M301218200]
Sugiura, N., Patel, R. G., Corriveau, R. A. N-methyl-D-aspartate receptors regulate a group of transiently expressed genes in the developing brain. J. Biol. Chem. 276: 14257-14263, 2001. [PubMed: 11297529] [Full Text: https://doi.org/10.1074/jbc.M100011200]