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.
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References
Bienvenut WV, Sumpton D, Martinez A, et al. Comparative large scale characterization of plant versus mammal proteins reveals similar and idiosyncratic N-alpha-acetylation features. Mol Cell Proteom. 2012;11:M111 015131.
Arnesen T, Van Damme P, Polevoda B, et al. Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. Proc Natl Acad Sci USA. 2009;106:8157–62.
Scott DC, Monda JK, Bennett EJ, Harper JW, Schulman BA. N-terminal acetylation acts as an avidity enhancer within an interconnected multiprotein complex. Science. 2011;334:674–8.
Behnia R, Panic B, Whyte JR, Munro S. Targeting of the Arf-like GTPase Arl3p to the Golgi requires N-terminal acetylation and the membrane protein Sys1p. Nat Cell Biol. 2004;6:405–13.
Forte GM, Pool MR, Stirling CJ. N-terminal acetylation inhibits protein targeting to the endoplasmic reticulum. PLoS Biol. 2011;9:e1001073.
Setty SR, Strochlic TI, Tong AH, Boone C, Burd CG. Golgi targeting of ARF-like GTPase Arl3p requires its Nalpha-acetylation and the integral membrane protein Sys1p. Nat Cell Biol. 2004;6:414–9.
Holmes WM, Mannakee BK, Gutenkunst RN, Serio TR. Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding. Nat Commun. 2014;5:4383.
Hwang CS, Shemorry A, Varshavsky A. N-terminal acetylation of cellular proteins creates specific degradation signals. Science . 2010;327:973–7.
Shemorry A, Hwang CS, Varshavsky A. Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway. Mol Cell. 2013;50:540–51.
Mullen JR, Kayne PS, Moerschell RP, et al. Identification and characterization of genes and mutants for an N-terminal acetyltransferase from yeast. EMBO J. 1989;8:2067–75.
Park EC, Szostak JW. ARD1 and NAT1 proteins form a complex that has N-terminal acetyltransferase activity. EMBO J. 1992;11:2087–93.
Arnesen T, Anderson D, Baldersheim C, Lanotte M, Varhaug JE, Lillehaug JR. Identification and characterization of the human ARD1-NATH protein acetyltransferase complex. Biochem J. 2005;386(Pt 3):433–43.
Ingram AK, Cross GAM, Horn D. Genetic manipulation indicates that ARD1 is an essential N-alpha-acetyltransferase in Trypanosoma brucei. Mol Biochem Parasit. 2000;111:309–17.
Sonnichsen B, Koski LB, Walsh A, et al. Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans. Nature. 2005;434:462–9.
Wang Y, Mijares M, Gall MD, et al. Drosophila variable nurse cells Encodes Arrest Defective 1 (ARD1), the catalytic subunit of the major N-terminal acetyltransferase complex. Dev Dyn. 2010;239:2813–27.
Ree R, Myklebust LM, Thiel P, Foyn H, Fladmark KE, Arnesen T. The N-terminal acetyltransferase Naa10 is essential for zebrafish development. Biosci Rep. 2015 Sep 18;35:e00249.
Kalvik TV, Arnesen T. Protein N-terminal acetyltransferases in cancer. Oncogene. 2013;32:269–76.
Arnesen T, Gromyko D, Pendino F, Ryningen A, Varhaug JE, Lillehaug JR. Induction of apoptosis in human cells by RNAi-mediated knockdown of hARD1 and NATH, components of the protein N-alpha-acetyltransferase complex. Oncogene. 2006;25:4350–60.
Gromyko D, Arnesen T, Ryningen A, Varhaug JE, Lillehaug JR. Depletion of the human Nalpha-terminal acetyltransferase A induces p53-dependent apoptosis and p53-independent growth inhibition. Int J Cancer. 2010;127:2777–89.
Lim JH, Park JW, Chun YS. Human arrest defective 1 acetylates and activates beta-catenin, promoting lung cancer cell proliferation. Cancer Res. 2006;66:10677–82.
Rope AF, Wang K, Evjenth R, et al. Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. Am J Hum Genet. 2011;89:28–43.
Van Damme P, Stove SI, Glomnes N, Gevaert K, Arnesen T. A Saccharomyces cerevisiae model reveals in vivo functional impairment of the Ogden syndrome N-terminal acetyltransferase NAA10 Ser37Pro mutant. Mol Cell Proteom. 2014;13:2031–41.
Myklebust LM, Van Damme P, Stove SI, et al. Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects. Human Mol Genet. 2015;24:1956–76.
Casey JP, Stove SI, McGorrian C, et al. NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment. Sci Rep. 2015;5:16022.
Popp B, Stove SI, Endele S, et al. De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females. Eur J Human Genet. 2015;23:602–9.
Saunier C, Stove SI, Popp B, et al. Expanding the phenotype associated with NAA10-related N-terminal acetylation deficiency. Hum Mutat. 2016;37:755–64.
Sidhu M, Brady L, Tarnopolsky M, Ronen GM. Clinical manifestations associated with the N-terminal-acetyltransferase NAA10 gene mutation in a girl: Ogden syndrome. Pediatr Neurol. 2017. Nov;76:82–85
Esmailpour T, Riazifar H, Liu LN, et al. A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome. J Med Genet. 2014;51:185–96.
Forrester S, Kovach MJ, Reynolds NM, Urban R, Kimonis V. Manifestations in four males with and an obligate carrier of the Lenz microphthalmia syndrome. Am J Med Genet. 2001;98:92–100.
Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674–82.
Eldomery MK, Coban-Akdemir Z, Harel T, et al. Lessons learned from additional research analyses of unsolved clinical exome cases. Genome Med. 2017;9:26.
Reid JG, Carroll A, Veeraraghavan N, et al. Launching genomics into the cloud: deployment of Mercury, a next generation sequence analysis pipeline. BMC Bioinform. 2014;15:30.
Larkin MA, Blackshields G, Brown NP, et al. Clustal W and Clustal X version 2.0. Bioinformatics. 2007;23:2947–8.
Robert X, Gouet P. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014;42:W320–324. (Web Server issue)
Drazic A, Arnesen T. [14C]-Acetyl-coenzyme A-based in vitro N-terminal acetylation assay. Methods Mol Biol. 2017;1574:1–8.
Van Damme P, Evjenth R, Foyn H, et al. Proteome-derived peptide libraries allow detailed analysis of the substrate specificities of N{alpha}-acetyltransferases and point to hNaa10p as the post-translational actin N{alpha}-acetyltransferase. Mol Cell Proteom. 2011;10:M110 004580.
Qian X, Li X, Cai Q, et al. Phosphoglycerate kinase 1 phosphorylates Beclin1 to induce autophagy. Mol Cell. 2017;65:917–31 e916.
Yoon H, Kim HL, Chun YS, et al. NAA10 controls osteoblast differentiation and bone formation as a feedback regulator of Runx2. Nat Commun. 2014;5:5176.
Lee CC, Peng SH, Shen L, et al. The Role of N-alpha-acetyltransferase 10 protein in DNA methylation and genomic imprinting. Mol Cell. 2017;68:89–103 e107.
Liszczak G, Goldberg JM, Foyn H, Petersson EJ, Arnesen T, Marmorstein R. Molecular basis for N-terminal acetylation by the heterodimeric NatA complex. Nat Struct Mol Biol. 2013;20:1098–105.
Magin RS, Liszczak GP, Marmorstein R. The molecular basis for histone H4- and H2A-specific amino-terminal acetylation by NatD. Structure. 2015;23:332–41.
Liszczak G, Arnesen T, Marmorstein R. Structure of a ternary Naa50p (NAT5/SAN) N-terminal acetyltransferase complex reveals the molecular basis for substrate-specific acetylation. J Biol Chem. 2011;286:37002–10.
Stove SI, Magin RS, Foyn H, Haug BE, Marmorstein R, Arnesen T. Crystal structure of the Golgi-associated human Nalpha-acetyltransferase 60 reveals the molecular determinants for substrate-specific acetylation. Structure. 2016;24:1044–56.
McTiernan N, Støve SI, Aukrust I, Mårli MT, Myklebust LM, Houge G, Arnesen T. NAA10 dysfunction with normal NatA-complex activity in a girl with non-syndromic ID and a de novo NAA10 p.(V111G) variant - a case report. BMC Med Genet. 2018;19:47.
Acknowledgements
We are very grateful for the participation of the two families that are involved in this study. The work has been supported by the Research Council of Norway (Project 249843), the Norwegian Health Authorities of Western Norway (Project 912176), and Bergen Research Foundation (BFS). The Baylor-Hopkins Center for Mendelian Genomics (BHCMG) has been funded by the US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) grant number UM1HG006542
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Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of the Baylor Genetics (BG), which performs clinical exome sequencing. JRL serves on the Scientific Advisory Board of BG. JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc., and is a coinventor of US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. All the remaining authors declare that they have no conflict of interest.
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Støve, S.I., Blenski, M., Stray-Pedersen, A. et al. A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy. Eur J Hum Genet 26, 1294–1305 (2018). https://doi.org/10.1038/s41431-018-0136-0
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DOI: https://doi.org/10.1038/s41431-018-0136-0
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