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Eur J Hum Genet. 2018 Sep;26(9):1294-1305. doi: 10.1038/s41431-018-0136-0. Epub 2018 May 10.

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

Author information

1
Department of Biological Sciences, University of Bergen, 5020, Bergen, Norway.
2
Department of Surgery, Haukeland University Hospital, 5021, Bergen, Norway.
3
Department of Biomedicine, University of Bergen, 5020, Bergen, Norway.
4
Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, 0424, Oslo, Norway.
5
Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway.
6
Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
7
University of Oklahoma School of Medicine, Oklahoma City, OK, USA.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
9
Human Genome Sequencing Center of Baylor College of Medicine, Houston, TX, 77030, USA.
10
Section of Pediatric Cardiology, Translational Biology and Molecular Medicine, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77055, USA.
11
Department of Pediatrics Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA.
12
Department of Biological Sciences, University of Bergen, 5020, Bergen, Norway. Thomas.Arnesen@uib.no.
13
Department of Surgery, Haukeland University Hospital, 5021, Bergen, Norway. Thomas.Arnesen@uib.no.
14
Department of Biomedicine, University of Bergen, 5020, Bergen, Norway. Thomas.Arnesen@uib.no.

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.

PMID:
29748569
PMCID:
PMC6117304
[Available on 2019-09-01]
DOI:
10.1038/s41431-018-0136-0
[Indexed for MEDLINE]

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