Uncovering molecular mechanisms involved in Ogden syndrome
First published at UiB.no December 10, 2014.
Line Merethe Myklebust and Svein Isungset Støve
This week, Line Merethe Myklebust, Svein Isungset Støve and colleagues in the Arnesen and Reuter groups of the Protein modifications, Metabolism and Disease (ProtMetD) research programme at MBI, presented novel findings on the Ogden syndrome in Human Molecular Genetics.
Ogden Syndrome
The lethal Ogden syndrome originally affecting several infant males in the town of Ogden (Utah) was revealed in 2011. These boys all carried a mutation in a gene named NAA10. NAA10 encodes an enzyme responsible for a cellular process called N-terminal acetylation, in which the majority of our proteins are attached a small label (an acetyl group) at their tip (the N-terminus). This modification can be crucial for the protein’s ability to function.
Boys affected by the Ogden syndrome have severe global developmental delays, reduced muscle strength, cardiac arrhythmias and craniofacial anomalies. All of the boys died before two years of age. So far eight boys from two unrelated families have been diagnosed with Ogden syndrome, caused by a point mutation in the gene NAA10 encoding the catalytic subunit of the NatA complex.
Presents novel findings
This week, Line Merethe Myklebust, Svein Isungset Støve and colleagues in the Arnesen and Reuter groups of the Protein modifications, Metabolism and Disease (ProtMetD) research programme at MBI, presented novel findings on the Ogden syndrome in Human Molecular Genetics. The molecular defects of the Naa10 protein causing this disease as well as the downstream cellular implications were studied by approaches within structural modelling, biochemistry, molecular biology, cell biology as well as proteomics by the ProtMetD-researchers in collaboration with a team of scientists from Gent University (VIB), Cold Spring Harbor Laboratory, University of Pennsylvania, and the Department of Surgery HUS. Analysis of patient-derived cells revealed that N-terminal acetylation was impaired in Ogden syndrome affected males thus revealing the in vivoimportance of N-terminal acetylation in human physiology and disease.
Recently, the teams in Bergen and Gent also presented a yeast Ogden syndrome model supporting the current findings. Although this disease is very rare, there are now several new cases emerging where children with various pathological manifestations are found to possess a mutation in the NAA10 gene including a recent study from Germany.
The co-first author, researcher Line Merethe Myklebust at ProtMetD/MBI, will in January 2015 initiate her BFS-fellowship to study the relationship between Naa10 and cancer and develop NAT-inhibitors for the potential use in future cancer chemotherapy.
Co-first author, PhD-student Svein Isungset Støve at ProtMetD/MBI and Dept. of Surgery HUS, will defend his PhD-thesis early 2015.
Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects
Myklebust LM, Van Damme P, Støve SI, Dörfel MJ, Abboud A, Kalvik TV, Grauffel C, Jonckheere V, Wu Y, Swensen J, Kaasa H, Liszczak G, Marmorstein R, Reuter N, Lyon GJ, Gevaert K, Arnesen T
Hum Mol Genet. 2015 Apr 1;24(7):1956-76.