Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency-Reference-Cited by-同舟云学术

Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency

Published:2021-04-16 Issue:8 Volume:128 Page:1156-1169
ISSN:0009-7330
Container-title:Circulation Research
language:en
Short-container-title:Circ Res

Author:

Ward Tarsha¹,Tai Warren¹,Morton Sarah¹²^ORCID,Impens Francis³⁴⁵,Van Damme Petra⁶,Van Haver Delphi³⁴⁵^ORCID,Timmerman Evy³⁴⁵,Venturini Gabriela¹⁷^ORCID,Zhang Kehan⁸⁹^ORCID,Jang Min Young¹,Willcox Jon A.L.¹^ORCID,Haghighi Alireza¹¹⁰¹¹^ORCID,Gelb Bruce D.¹²,Chung Wendy K.¹³^ORCID,Goldmuntz Elizabeth¹⁴,Porter George A.¹⁵,Lifton Richard P.¹⁶¹⁷,Brueckner Martina¹⁶¹⁸,Yost H. Joseph¹⁹,Bruneau Benoit G.²⁰,Gorham Joshua¹,Kim Yuri¹²¹^ORCID,Pereira Alexandre¹,Homsy Jason¹,Benson Craig C.¹,DePalma Steven R.¹^ORCID,Varland Sylvia²²²³²⁴^ORCID,Chen Christopher S.⁸⁹,Arnesen Thomas²²²³²⁵^ORCID,Gevaert Kris⁵,Seidman Christine¹¹⁰¹¹^ORCID,Seidman J.G.¹^ORCID

Affiliation:

1. Genetics (T.W., W.T., S.M., G.V., M.Y.J., J.A.L.W., A.H., J.G., Y.K., A.P., J.H., C.C.B., S.R.D., C.S., J.G.S.), Harvard Medical School.

2. Division of Newborn Medicine, Boston Children’s Hospital (S.M.).

3. VIB Center for Medical Biotechnology, B-9000 Ghent, Belgium (F.I., D.V.H., E.T., K.G.).

4. VIB Proteomics Core, B-9000 Ghent, Belgium (F.I., D.V.H., E.T.).

5. Biomolecular Medicine (F.I., D.V.H., E.T., K.G.), Ghent University, B-9000 Ghent, Belgium.

6. Biochemistry and Microbiology (P.V.D.), Ghent University, B-9000 Ghent, Belgium.

7. University of Sao Paulo (G.V.).

8. Biomedical Engineering, Boston University, MA (K.Z., C.S.C.).

9. The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA (K.Z., C.S.C.).

10. Howard Hughes Medical Institute (A.H., C.S.), Harvard Medical School.

11. Medicine, Brigham and Women’s Hospital (A.H., C.S.).

12. Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (B.D.G.).

13. Pediatrics and Medicine, Columbia University Medical Center, New York (W.K.C.).

14. Cardiology, Children’s Hospital of Philadelphia, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia (E.G.).

15. Pediatrics, University of Rochester Medical Center (G.A.P.).

16. Genetics, Yale University School of Medicine, New Haven (R.P.L., M.B.).

17. Laboratory of Human Genetics and Genomics, Rockefeller University, New York (R.P.L.).

18. Pediatrics, Yale University School of Medicine, New Haven (M.B.).

19. Molecular Medicine Program, University of Utah, Salt Lake City (H.J.Y.).

20. Gladstone Institutes, San Francisco, CA (B.G.B.).

21. Division of Cardiovascular Medicine, Brigham and Women’s Hospital (Y.K.).

22. Biomedicine (S.V., T.A.), University of Bergen, N-5020 Bergen, Norway.

23. Biological Sciences (S.V., T.A.), University of Bergen, N-5020 Bergen, Norway.

24. Donnelly Centre for Cellular and Biomolecular Research, Toronto, Canada (S.V.).

25. Surgery, Haukeland University Hospital, N-5021 Bergen, Norway (T.A.).

Abstract

Rationale: NAA15 (N-alpha-acetyltransferase 15) is a component of the NatA (N-terminal acetyltransferase complex). The mechanism by which NAA15 haploinsufficiency causes congenital heart disease remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective: We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity and identifying proteins dependent upon a full amount of NAA15. Methods and Results: We introduced heterozygous loss of function, compound heterozygous, and missense residues (R276W) in iPSCs using CRISPR/Cas9. Haploinsufficient NAA15 iPSCs differentiate into cardiomyocytes, unlike NAA15 -null iPSCs, presumably due to altered composition of NatA. Mass spectrometry analyses reveal ≈80% of identified iPSC NatA targeted proteins displayed partial or complete N-terminal acetylation. Between null and haploinsufficient NAA15 cells, N-terminal acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W induced pluripotent stem cells. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; 18 were ribosomal-associated proteins. At least 4 proteins were encoded by genes known to cause autosomal dominant congenital heart disease. Conclusions: These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and N-terminal acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated congenital heart disease. Additionally, genetically engineered induced pluripotent stem cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function.

Funder

HHS | NIH | National Heart, Lung, and Blood Institute

Fondation Leducq

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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