Naa10 in development and disease.

Identification of causative mutations for rare genetic diseases has for long been of interest to medical geneticists. New developments within next generation sequencing have resulted in a huge increase in discovered pathogenic mutations. This is of great importance as it is the first step in the process of understanding the underlying mechanisms of different disorders. In 2011, such a sequencing study led to the identification of a point mutation in the N-terminal acetyltransferase Naa10 as the cause of a previously undescribed lethal disorder called Ogden Syndrome [1]. The NAA10 gene was previously found to be overexpressed in different types of cancer, but its dysfunction had never before been shown to cause disease. The vast majority of proteins undergo a broad range of chemical modifications either during or after their biosynthesis. These modifications increase the diversity of expressed proteins and are often crucial for their regulation and function. Protein Nα-terminal acetylation (Nt-acetylation) represents one such major modification affecting 80-90% of all soluble human proteins [2]. The N-terminal acetyltransferases (NATs) catalyze this reaction and transfer the acetyl moiety from acetyl-coenzyme A to the Nα-group of proteins’ N-termini. In humans, six NAT enzymes (NatA-NatF) exist, acetylating defined sets of substrates [3]. Naa10 constitute the catalytic subunit of the NatA complex, the major NAT acetylating 40% of all cellular proteins [2]. Ogden syndrome is an X-linked disorder characterized by severe global developmental delays, craniofacial anomalies, hypotonia, cardiac arrhythmia and eventual cardiomyopathy, resulting in mortality during infancy [1]. Our recent study highlights the molecular defects of the Naa10S37P variant causing the Ogden syndrome as well as the downstream cellular implications [4]. The mutant NatA complex displayed both an impaired peptide substrate binding and NAT activity (Figure 1) and furthermore, we observed a significantly reduced NatA complex formation. Our proteomic studies demonstrated a reduced Nt-acetylation level in both B-cells and fibroblasts derived from individuals with Ogden syndrome, while female carriers and wildtype family members had unchanged Nt-acetylation levels. This is the first time a human pathological condition has been linked to altered Nt-acetylation patterns. Interestingly, we observed a reduced Nt-acetylation only for a specific subset of the proteome matching the specificity of the NatA complex, thus supporting that NatA mediated acetylation is specifically perturbed in vivo in Ogden syndrome males. Ogden syndrome cells had a reduced growth rate and were less viable when cultured dispersed and stressed, but more metabolically active when kept in a dense culture. While wildtype cells entered the G0 phase, S37P cells continued to proliferate and showed a partial loss of cell-to-cell contact inhibition. Naa10 is a key player in a variety of cellular pathways [3] and markers for these were investigated in Ogden syndrome cells. S37P cells revealed an increased expression of Retinoblastoma 1 (RB1), a known negative regulator of the cell cycle. Other pathways previously linked to Naa10 function such as β-catenin, Cyclin D, TSC2/mTOR/pS6K1, MYLK and β-PIX were not perturbed in S37P cells. Several studies of female carriers of X-linked mutations have shown a skewed X-chromosome inactivation, a process occurring during early development Editorial