This website uses cookies to ensure you get the best experience on our website.
- Table of Contents
Facts about N-alpha-acetyltransferase 15, NatA auxiliary subunit.
Required to control retinal neovascularization in adult ocular endothelial cells. In complex with XRCC6 and XRCC5 (Ku80), up-regulates transcription from the osteocalcin promoter.
Mouse | |
---|---|
Gene Name: | Naa15 |
Uniprot: | Q80UM3 |
Entrez: | 74838 |
Belongs to: |
---|
No superfamily |
FLJ13340; GA19; Gastric cancer antigen Ga19; N(alpha)-acetyltransferase 15, NatA auxiliary subunit; NARG1; NATHGa19; NMDA receptor-regulated protein 1; N-terminal acetyltransferase; Protein tubedown-1; Tbdn100; TBDN100NatA auxiliary subunit; transcriptional coactivator tubedown-100; tubedown-1
Mass (kDA):
100.961 kDA
Mouse | |
---|---|
Location: | 3|3 C |
Sequence: | 3; |
Endothelial cells, osteoblasts and myeloid cells of the hematopoietic tissue. Present in adult ovary, bone marrow, brain, heart, kidney, testis and osteoblasts.
The most common use of the NAA15 marker is in the treatment of individuals with Ogden syndrome. This gene codes for a protein that is involved in NatA-mediated N-terminal acetylation. The protein also modifies other proteins. As genetic sequencing becomes cheaper and more available, it may become possible to detect disorders caused by rare mutations of the NAA15 gene. Lyon expects to see more patients with rare mutations in the future.
The NAA15 gene is one of the many dsRNAs that can be produced in a variety of ways. The molecule is formed from a single strand of RNA that forms a hairpin, the complementary ssRNA, or expression from a DNA vector. Its primary role is in the production of RNAs that are used in a variety of applications.
Functional studies of the NAA15 gene have revealed its cytoplasmic localization. In addition, this marker's bimolecular fluorescence complementation assay has revealed its association with ribosomes. In yeast, it co-fractionates with the ribosomal protein S14. These findings suggest that the NAA15 gene may be involved in ribosomal protein deposition and associated with ribosomes.
Originally identified in zebrafish, the NAA15 gene encodes a protein of unknown function. It is most likely an N-acetyltransferase. The gene NAA15 was first discovered through a teleost genome duplication, and the corresponding protein was identified as a result. The protein has numerous functions in regulating the development of different tissues, including the myotome.
However, previous studies have linked the NAA15 gene to neurodevelopmental and motor delay. Four out of 38 individuals analyzed with the NAA15 mutation also had some heart defects. This study, therefore, suggests that the mutation may be linked to autism and intellectual disability. In addition, previous studies have linked NAA15 to heart defects. These results, however, are not conclusive. The study needs to be replicated in more individuals before the final conclusions are made.
The acetylation of proteins in human cells is regulated by a subset of Nats. Interestingly, the interaction between NAA10 and NAA15 can regulate the active site of NAA10, a Nat that binds to the ribosome. Although this interaction is not completely understood, it appears to be essential in ribosome attachment. Despite the lack of understanding of the regulatory mechanisms in the case of these two Nats, the NAA15 marker is still a key gene for ribosome attachment and acetylation.
Functional studies of the NAA15 gene have suggested that this gene may play an important role in the regulation of protein quality. Because NatA activity regulates the activities of a wide range of transcription factors in plants, it may be involved in the control of the drought response. However, this pathway is regulated by the stress-dedicated phytohormone ABA. A decrease in NatA in planta will induce the canonical drought stress response. Further, it down regulates numerous biosynthesis pathways, including ABA.
Human iPSCs with reduced levels of the NAA15 protein were produced using the personal genome project, a platform that enables scientists to manipulate the DNA sequence of a cell's genome in real time. Using CRISPR/Cas9 gene editing, two independent cell lines were generated for genotypes NAA15+/-, NAA15-/-, and NAA15+/R276W. Sanger sequencing was used to verify mutations and next-generation sequencing was used to verify PCR amplified products.
In a recent study, scientists sequenced the NAA15 gene in 13,000 individuals and identified 13 harmful mutations. To do this, the researchers combed large databases of genetic information relating to people with developmental disorders. They registered these patients with the GeneMatcher program, which matches scientists to people with mutations of genes of interest. They also collected information from clinicians and geneticists about the characteristics of people with mutations of the NAA15 gene.
The genetic variation of NAA15 in human iPSCs was examined for pathogenicity. Exome sequencing showed that NAA15 haploinsufficiency caused decreased expression of four proteins coding for autosomal dominant CHD genes. Moreover, mutations of the NAA15 marker in human iPSCs have minimal effect on the transcriptome, although they impair cardiac function. Using genetically engineered iPSCs for clinical research, researchers hope to identify mutations that contribute to cardiac abnormalities and identify benign variants in the gene.
The expression levels of NAA15 in mutant and WT iPSCs were compared using shotgun proteomics. Those with reduced levels of NAA15 exhibited NatA-like substrate specificity, and more than half of the mutant samples had an alanine residue at position 2 or three. However, the distribution of N-terminal residues was similar in NAA15+/ and NAA15-/ iPSCs.
Recently, we have investigated the role of the NAA15 marker in the Ogden syndrome. In a heterologous yeast model, we showed that overexpressing Naa10-WT partially rescues the migration phenotype of the disease. Our findings suggest that the reduced catalytic activity and altered ability to form the NatA complex in the cells from Ogden syndrome patients may contribute to the disease.
Our family of patients with Ogden syndrome has tested females two times for X-inactivation. We then used immortalized B cells from our family members for western blotting analysis. To ensure equal protein loading, we used anti-b-tubulin antibody as a positive control. We then measured the expression of hNaa10 by densitometry using ImageJ. Because the alleles were so closely spaced, the sample was difficult to interpret.
We performed this experiment with the Nt-acetylated peptides from B cells of males with Ogden syndrome. We found that the acetylation levels of these peptides were reduced from fifty-five to seventy-six percent. Moreover, we found reduced Nt-acetylation of the commonly identified NatA and NatE-type substrates, indicating a lack of functional activity in the disease.
Genetic tests for Ogden syndrome included chromosome microarray, fragile-X testing, and an 18-gene panel for cardiomyopathy. We also confirmed the existence of the NAA10 variant through exome sequencing and other genetic tests. These studies are the first of their kind to reveal the role of the NAA15 marker in Ogden syndrome. These studies may help clinicians find the right treatment for patients with the disease.
Ogden syndrome is an X-linked lethal condition associated with a mutation in the NAT gene. A mutation in the Naa10 gene affects the catalytic subunit of the NAT complex in human males. A structural model of the human protein reveals differences in catalysis and the interface between the auxiliary subunit hNaa15 and the main human NAT, the hNaa15. In addition to these differences, biochemical data suggest that the S37P mutant has impaired interaction with the NatA50, which is another interrogator of the complex.
Among these patients, the NAA15 gene is found in approximately 5% of cases. It is considered rare, but has the potential to affect children with this genetic syndrome. This disease is characterized by a number of characteristics, including facial grima and stuttering. Patients with this condition usually have a short columella and are incontinent. This marker has been used to detect the presence of this de novo variant in the gene.
PMID: 12145306 by Willis D.M., et al. Regulation of osteocalcin gene expression by a novel Ku antigen transcription factor complex.
PMID: 12888564 by Sugiura N., et al. An evolutionarily conserved N-terminal acetyltransferase complex associated with neuronal development.