| dc.description.abstract | Approximately 80-90 % of all eukaryotic proteins are co- or post-translationally acetylated on their N-terminus by a group of enzymes called N-terminal acetyltransferases (NATs) (Arnesen et al., 2009). To date, eight NATs have been identified in eukaryotes, seven of which (NatA-NatF and NatH) are found in humans. Each of the NATs differ in subunit composition and have a distinct substrate specificity (Aksnes et al., 2019). The NatA complex is conserved from yeast to humans, acetylating approximately 40 % of the human proteome (Arnesen et al., 2009). NatA is composed of the catalytic subunit NAA10 and the auxiliary subunit NAA15 and has the broadest substrate specificity among the NATs (Arnesen et al., 2005a, Liszczak et al., 2013). In 2011, Rope et al., reported a NAA10 S37P missense mutation to be the cause of the lethal X-linked disorder named Ogden syndrome (Rope et al., 2011). Some years later, Esmailpour and colleagues reported that the genetically heterogeneous X-linked disorder Lenz microphtalmia syndrome (LMS) was caused by a splice mutation in NAA10 (Esmailpour et al., 2014). The last decade, several other NAA10 mutations have been reported to have pathological effects in the harboring patient. Intellectual disability, development delay, growth deficiency and cardiac and skeletal anomalies are among the most common phenotypes coupled to NAA10 deficiency. The focus of this thesis has been to functionally characterize two missense mutations in NAA10 suspected to cause disease in humans. These mutations are NAA10 L11R and NAA10 H16P, which were identified in female patients presenting with some symptoms typical of NAA10 deficiency. NatA complex formation and in vitro intrinsic catalytic activity, and cellular stability have been characterized, and bioinformatic analyses have been performed. The work presented in this thesis demonstrates that the NAA10 L11R variant and H16P variants have a reduced NatA complex formation and their NatA activity is functionally impaired. The L11R variant affects NatA activity to a smaller extent than the H16P mutation. In the cellular stability assay, the NAA10 L11R had a destabilizing effect, whereas NAA10 H16P appears stable and is unlikely to affect neither monomeric NAA10 nor NatA stability. The study presented in this thesis support that these variants are pathological, yet further studies are needed to define the detailed underlying mechanisms. | en_US |
