TY - JOUR T1 - Proteomic and genomic characterization of a yeast model for Ogden syndrome JF - bioRxiv DO - 10.1101/045047 SP - 045047 AU - Max J. Döerfel AU - Han Fang AU - Jonathan Crain AU - Michael Klingener AU - Jake Weiser AU - Gholson J. Lyon Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/05/03/045047.abstract N2 - Naa10 is a Nα-terminal acetyltransferase that, in a complex with its auxiliary subunit Naa15, co-translationally acetylates the α-amino group of newly synthetized proteins as they emerge from the ribosome. Roughly 40-50% of the human proteome is acetylated by Naa10, rendering this an enzyme with one of the most broad substrate specificities known. Despite this, very little is known about the functional consequences of this modification. Recently, we reported an X-linked disorder of infancy, Ogden syndrome, in two families harboring a c.109T>C (p.Ser37Pro) variant in NAA10. In the present study we performed in-depth characterization of a yeast model of Ogden syndrome. Stress tests and proteomic analyses suggest that the S37P mutation disrupts Naa10 function thereby reducing cellular fitness, possibly due to an impaired functionality of molecular chaperones, Hsp104, Hsp40 and the Hsp70 family. Microarray and RNA-seq revealed a pseudo-diploid gene expression profile in ΔNaa10 cells, likely responsible for a mating defect due to reduced N-terminal acetylation of the Naa10 substrates Orcl and Sir3. In conclusion, the data presented here further support the disruptive nature of the S37P/Ogden mutation and identify affected cellular processes, potentially contributing to the severe phenotype seen in Ogden syndrome. ER -