A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy

Abstract

The NAA10-NAA15 complex (NatA) is an N-terminal acetyltransferase that catalyzes N-terminal acetylation of ~40% of all human proteins. N-terminal acetylation has several different roles in the cell, including altering protein stability and degradation, protein localization and protein-protein interactions. In recent years several X-linked NAA10 variants have been associated with genetic disorders. We have identified a previously undescribed NAA10 c.215T>C p.(Ile72Thr) variant in three boys from two unrelated families with a milder phenotypic spectrum in comparison to most of the previously described patients with NAA10 variants. These boys have development delay, intellectual disability, and cardiac abnormalities as overlapping phenotypes. Functional studies reveal that NAA10 Ile72Thr is destabilized, while binding to NAA15 most likely is intact. Surprisingly, the NatA activity of NAA10 Ile72Thr appears normal while its monomeric activity is decreased. This study further broadens the phenotypic spectrum associated with NAA10 deficiency, and adds to the evidence that genotype-phenotype correlations for NAA10 variants are much more complex than initially anticipated.

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

“…Because Phe128 is located in a hydrophobic pocket at the core of NAA10, the Phe128Leu mutation was predicted to destabilize the fold and lead to a loss of enzymatic activity and stability, as was observed previously (Saunier et al, 2016). Some of these destabilizing variants, like NAA10 V111G and I72T, display interesting in vitro data, suggesting that, when bound to NAA15, the NatA complex NAT-activity is intact, whereas the monomeric catalytic activity is strongly impaired Støve et al, 2018).…”

N-terminal Acetylation Levels Are Maintained During Acetyl-CoA Deficiency in Saccharomyces cerevisiae

“…The herein observed fluctuations in Nt-acetylation may be connected to studies performed in A. thaliana ( 17 ) and C. elegans ( 18 ), in which Nt-acetylation was linked to various stress responses and further supports a role for Nt-acetylation in stress resistance ( 17 , 18 ). Nt-acetylation is implicated in cardiac arrhythmia, developmental delay ( 20 , 78 – 84 ) and cancers ( 85 ). Identifying factors that regulate Nt-acetylation is therefore of great importance.…”

Investigating the functionality of a ribosome-binding mutant of NAA15 using Saccharomyces cerevisiae

“…N-terminal acetylation is carried out by a family of enzymes called N-terminal acetyltransferases (NATs). The biological importance of this protein modification is underscored by the fact that dysfunctional NATs are implicated in a variety of developmental disorders and cancers [ 24 – 33 ].…”