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

Myklebust, L. M., Van Damme, P., Stove, S. I., Dorfel, M. J., Abboud, A., Kalvik, T. V., Grauffel, C., Jonckheere, V., Wu, Y., Swensen, J., Kaasa, H., Liszczak, G., Marmorstein, R., Reuter, N., Lyon, G. J., Gevaert, K., Arnesen, T. (December 2014) Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects. Human Molecular Genetics, 24 (7). pp. 1956-1976. ISSN 0964-6906

DOI: 10.1093/hmg/ddu611


The X-linked lethal Ogden syndrome was the first reported human genetic disorder associated with a mutation in an N-terminal acetyltransferase (NAT) gene. The affected males harbour a Ser37Pro mutation in the gene encoding hNaa10, 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 Ser37Pro mutant highlight differences in regions involved in catalysis and at the interface between hNaa10 and the auxiliary subunit hNaa15. Biochemical data further demonstrate a reduced catalytic capacity and an impaired interaction between hNaa10 Ser37Pro and hNaa15 as well as hNaa50 (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/NatE-type 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.

Item Type: Paper
Subjects: diseases & disorders > congenital hereditary genetic diseases
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > N-terminal acetylation
CSHL Authors:
Communities: CSHL labs > Lyon lab
Stanley Institute for Cognitive Genomics
Depositing User: Matt Covey
Date: 8 December 2014
Date Deposited: 19 Dec 2014 17:15
Last Modified: 06 Nov 2015 20:43
PMCID: PMC4355026
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