PROJECT SUMMARY
Although the scientific community has made substantial progress in elucidating the function of many genes,
much remains unknown, particularly concerning the diversity introduced into proteins with co- and post-
translational modifications. One such modification is amino-terminal acetylation (NTA), which is considerably
understudied, with very few reports on the mammalian N-terminome. Protein acetylation occurs both at lysine
residues within proteins (lysine acetylation or N-e-acetylation) and at the N-terminus of proteins (Nt-acetylation
or N-¿-acetylation). Protein Nt-acetylation is among the most common modifications of eukaryotic proteins and
is carried out by N-terminal acetyltransferases (NATs). The knockdown phenotypes of human NATs in cell culture
suggest that protein NTA is an essential modification in human cells to maintain proliferation, but functional
insights and mammalian in vivo models are lacking. Understanding of a general role for NTA remains elusive,
and only a few examples in which NTA affects protein function, complex formation, activity, or stability are known.
My laboratory discovered and characterized the first genetic disease coupled to N-terminal acetylation (NTA) of
proteins, involving a missense mutation in the X-linked gene NAA10; we named this rare disease Ogden
syndrome (OS) in honor of the hometown (Ogden, Utah), where the first family we identified with OS lived. The
affected boys have a distinct combination of craniofacial anomalies, hypotonia, global developmental delays,
cryptorchidism, cardiac anomalies, and cardiomegaly. We and others then found more than a dozen families
with overlapping phenotypes with additional mutations in NAA10 in this pathway; we also reported recently that
de novo mutations in NAA15, encoding a binding partner for NAA10, are involved in congenital heart defects
and/or neurodevelopment. This finding is consistent with the range of cardiac anomalies and
neurodevelopmental delays seen in OS (now more broadly known as NAA10-related disorders). As part of our
long-term focus on the mechanistic dissection of NTA, over the next five years, we will focus on detailed
phenotyping of humans with mutations in the pathway, alongside a systems-level study of unique mouse models,
including conditional alleles, using histologic and functional approaches to provide the first mechanistic insights
into the role of NTA in cardiac development and mammalian physiology. We will also continue our analysis of a
newly identified enzyme in the pathway, which we propose compensates for and prevents embryonic lethality in
humans and mouse models with mutations in NAA10. This R35 grant will enable the study of the molecular
biology and pathophysiology associated with NAA10- and NAA15-related disorders and the NTA pathway, as
part of a sustained effort to understand the role of NTA in mammalian biology. These studies will be a critical
step toward revealing the role of NTA in human health and disease, as NTA has been linked to cancer
progression and neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Huntington’s diseases.