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

Line M. Myklebust, Petra Van Damme, Svein I. Støve, Max J. Dörfel, Angèle Abboud, Thomas V. Kalvik, Cedric Grauffel, Veronique Jonckheere, Yiyang Wu, Jeffrey Swensen, Hanna Kaasa, Glen Liszczak, Ronen Marmorstein, Nathalie Reuter, Gholson J. Lyon, Kris Gevaert, Thomas Arnesen

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


The X-linked lethal Ogden syndromewas the first reported human genetic disorder associated with a mutation in an N-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 and at the interface between Naa10 and the auxiliary subunit hNaa15. Biochemical data further demonstrate a reduced catalytic 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 and proliferation capacity, possibly linked to a perturbed retinoblastoma pathway. N-Terminal acetylation clearly plays a role in Ogden syndrome, thus revealing the in vivo importance of N-terminal acetylation in human physiology and disease.

Original languageEnglish (US)
Pages (from-to)1956-1976
Number of pages21
JournalHuman molecular genetics
Issue number7
StatePublished - Oct 28 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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