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Wiley, Human Mutation: Variation, Informatics and Disease, 8(37), p. 755-764, 2016

DOI: 10.1002/humu.23001

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Expanding the Phenotype Associated with NAA10 Related N-terminal Acetylation Deficiency

Journal article published in 2016 by Charlotte de Bie, Marjon van Slegtenhorst, Chloé Saunier, Svein Isungset Støve, Christel Thauvin-Robinet, Bernt Popp, Bénédicte Gérard, Kamer Tezcan, Marina Blenski, Charlotte Bie, Nicholas AhMew, Melissa Wasserstein, Julien Thevenon, Bruno Leheup, Laetitia Lampert and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

N-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, while de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We now identified three different novel and one known missense mutation in NAA10, de novo in eleven females, and due to maternal germ line mosaicism in another girl and her more severely affected and deceased brother. In vitro enzymatic assays for the novel, recurrent mutations p.(Arg83Cys) and p.(Phe128Leu) revealed reduced catalytic activity. X-inactivation was random in four females. The core phenotype of X-linked NAA10 related N-terminal-acetyltransferase deficiency in both males and females includes developmental delay, severe intellectual disability, postnatal growth failure with severe microcephaly and skeletal or cardiac anomalies. Genotype-phenotype correlations within and between both genders are complex and may include various factors such as location and nature of mutations, enzymatic stability and activity, and X-inactivation in females. This article is protected by copyright. All rights reserved.