Ogden Syndrome, also known as NAA10-related neurodevelopmental disorder, is an X-linked disease caused by pathologic variants in NAA10, the catalytic sub-unit of the NatA N-α-terminal acetyltransferase, and characterized by variable neurologic, behavioral, and cardiovascular deficits. We present the generation of 2 isogenic pairs of patient-derived iPSCs having a R83C mutation in NAA10. A male hemizygous NAA10 line which was corrected to WT, and a female heterozygous which was edited to be WT/WT as well as R83C/R83C. Combined with the published cohort of >30 NAA10-related syndrome patient iPSC lines and isogenic pairs it represents a powerful cohort to investigate NAA10-related syndrome (Wesely et al., 2024).

The catalytic subunit of NatA, the main component of the N-terminal acetyltransferase complex, which is involved in most of the acetylation of the human proteome, is encoded by the NAA10 gene. Mutations in the NAA10 gene lead to neurodegenerative diseases associated with disruption of acetylation. Ogden syndrome (OS) is a rare X-linked recessive or dominantly inherited disorder associated with NAA10 gene mutations, characterized by variable findings such as autism spectrum disorder, intellectual disability, and cardiac anomalies. In this article, it is aimed to clarify the functionality of two novel NAA10 gene variants in two female patients with OS. A whole-exome sequencing (WES) study was performed from the blood samples of the patients. The effects of the two variants found by tertiary structure modeling, protein stability analysis, and molecular docking analyses on NAA10 were examined. Autism, intellectual retardation, and epilepsy were prominent in the patients, and heterozygous variants c.346C>T and c.439A>T in the NAA10 gene were detected in WES. The clinical findings were compatible with OS. The p.Arg116Trp and p.Met147Leu changes in the NAA10 gene caused changes in the overall topological structure of NAA10, including the substrate and ligand binding site. In this study, c.346C>T and c.439A>T variants were found to alter the functional stability, structure, and energy of NAA10. Functional analyses of NAA10 variants in two rare OS patients have once again demonstrated that novel variants are essential studies for phenotype-genotype correlation association steps.

The NatA complex is composed of the NAA10, NAA15, and HYPK sub-units. It is primarily responsible for N-terminal acetylation, a critical post-translational modification in eukaryotes. Pathogenic variants within NAA10 cause Ogden Syndrome (OS), which is characterized by varying degrees of intellectual disability, hypotonia, developmental delay, and cardiac abnormalities. Although the cardiac manifestations of the disease have been described extensively in case reports, there has not been a study focusing on the cardiac manifestations and their recommended clinical cardiac management. In this study, we describe the cardiac manifestations of OS in a cohort of 85 probands. We found increased incidence of structural and electrophysiologic abnormalities, with particularly high prevalence of QT interval prolongation. Sub-analysis showed that male probands and those with variants within the NAA15-binding domain had more severe phenotypes than females or those with variants outside of the NAA15-binding domain. Our results suggest that an OS diagnosis should be accompanied by full cardiac workup with emphasis on echocardiogram for structural defects and EKG/Holter monitoring for electrophysiologic abnormalities. Additionally, we strongly recommend that the use of QT-prolonging drugs be followed up with routine electrophysiological monitoring or consultation with a pediatric cardiologist. We hope this study guides clinicians and caregivers treating patients with OS and moves the field toward a standardized diagnostic workup for patients with this condition.

NAA10 (N-alpha-acetyltransferase 10) is a pivotal enzyme in eukaryotic cells, serving as the catalytic subunit of the NatA complex, which is responsible for the N-terminal acetylation of approximately 40-50% of the human proteome. Beyond its canonical role in co-translational N-terminal acetylation, NAA10 also acetylates internal lysine residues of various proteins and exerts non-catalytic regulatory functions through diverse protein-protein interactions. Pathogenic variants in NAA10 are linked to a spectrum of developmental disorders, most notably Ogden syndrome, which is characterized by neurodevelopmental delay, cardiac defects, and craniofacial anomalies. In cancer, NAA10 is frequently overexpressed or genomically amplified, where its dysregulation correlates with tumor aggressiveness and poor prognosis. Functional studies implicate NAA10 in regulating cell cycle progression, apoptosis, migration, and other hallmarks of cancer. In this review, we summarize the structure, molecular mechanisms, and physiological functions of NAA10, as well as its roles in human diseases and cancer. We present in silico pan-cancer analyses that highlight its clinical significance and potential downstream pathways. Furthermore, we discuss the therapeutic potential and challenges of targeting NAA10 in cancer, and propose future research directions to better understand its multifaceted roles in health and disease.

The NatA complex is composed of the NAA10, NAA15, and HYPK subunits. It is primarily responsible for N-terminal acetylation, a critical post-translational modification in eukaryotes. Pathogenic variants within NAA10 cause Ogden Syndrome (OS), which is characterized by varying degrees of intellectual disability, hypotonia, developmental delay, and cardiac abnormalities. Although the cardiac manifestations of the disease have been described extensively in case reports, there has not been a study focusing on the cardiac manifestations and their recommended clinical cardiac management. In this study, we describe the cardiac manifestations of OS in a cohort of 85 probands. We found increased incidence of structural and electrophysiologic abnormalities, with particularly high prevalence of QT interval prolongation. Sub-analysis showed that male probands and those with variants within the NAA15-binding domain had more severe phenotypes than females or those with variants outside of the NAA15-binding domain. Our results suggest that an OS diagnosis should be accompanied by full cardiac workup with emphasis on echocardiogram for structural defects and EKG/Holter monitoring for electrophysiologic abnormalities. Additionally, we strongly recommend that the use of QT-prolonging drugs be followed up with routine electrophysiological monitoring or consultation with a pediatric cardiologist. We hope this study guides clinicians and caregivers treating patients with OS and moves the field toward a standardized diagnostic workup for patients with this condition.