Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects

TheX-linkedlethalOgdensyndromewasthe firstreportedhumangeneticdisorderassociatedwithamutationinanN-terminal acetyltransferase (NAT) gene. The affected males harbor an Ser37Pro (S37P) mutation in the gene encoding Naa10, the catalytic subunit of NatA, the major human NAT involved in the co-translational acetylation of proteins. Structural models and molecular dynamics simulations of the human NatA and its S37P mutant highlight differences in regions involved in catalysis andattheinterfacebetweenNaa10andtheauxiliarysubunithNaa15.Biochemical datafurtherdemonstratea reducedcatalytic capacity and an impaired interaction between hNaa10 S37P and Naa15 as well as Naa50 (NatE), another interactor of the NatA complex. N-Terminal acetylome analyses revealed a decreased acetylation of a subset of NatA and NatE substrates in Ogden syndrome cells, supporting the genetic findings and our hypothesis regarding reduced Nt-acetylation of a subset of NatA/NatEtype substrates as one etiology for Ogden syndrome. Furthermore, Ogden syndrome fibroblasts display abnormal cell migration