ClinVar

Rope et al. (2011) identified 2 unrelated families segregating a lethal X-linked disorder, Ogden syndrome (OGDNS; 300855). The 2 families had independent occurrences of a T-to-C transition at nucleotide 109 of the NAA10 gene, resulting in a serine-to-proline substitution at codon 37 (S37P). The NAA10 gene encodes the catalytic subunit of the N-terminal acetyltransferase. Substitution of proline for serine at position 37 is likely to affect structure, and in vitro assays of protein function demonstrated 60 to 80% reduction in NAT activity of the mutant protein toward the in vivo substrate RNase P protein p30 (606115). In contrast, the activity toward the substrate high mobility group protein A1 (600701) was reduced by only 20%.

Using structural modeling and simulations, Myklebust et al. (2015) found that S37P mutant NAA10 differs from wildtype NAA10 in regions involved in catalysis and at the interface between NAA10 and NAA15. The S37P mutation shortens helix alpha-2, weakens the interfacial hydrogen-bonding network, and reduces NAA10 flexibility. In vitro biochemical analysis demonstrated reduced substrate binding and catalytic capacity and impaired interaction between S37P mutant NAA10 and NAA15 (608000) or NAA50 (610834). Analysis of total protein N-acetylation in immortalized wildtype and Ogden syndrome B cells and fibroblasts revealed decreased acetylation of a subset of NatA and NatE substrates in Ogden syndrome cells. Furthermore, Ogden syndrome fibroblasts showed reduced cell migration and proliferation capacity, and elevated sensitivity to cell stresses.