TY - JOUR
T1 - Expanding the Phenotype Associated with NAA10-Related N-Terminal Acetylation Deficiency
AU - Saunier, Chloé
AU - Støve, Svein Isungset
AU - Popp, Bernt
AU - Gérard, Bénédicte
AU - Blenski, Marina
AU - AhMew, Nicholas
AU - de Bie, Charlotte
AU - Goldenberg, Paula
AU - Isidor, Bertrand
AU - Keren, Boris
AU - Leheup, Bruno
AU - Lampert, Laetitia
AU - Mignot, Cyril
AU - Tezcan, Kamer
AU - Mancini, Grazia M.S.
AU - Nava, Caroline
AU - Wasserstein, Melissa
AU - Bruel, Ange Line
AU - Thevenon, Julien
AU - Masurel, Alice
AU - Duffourd, Yannis
AU - Kuentz, Paul
AU - Huet, Frédéric
AU - Rivière, Jean Baptiste
AU - van Slegtenhorst, Marjon
AU - Faivre, Laurence
AU - Piton, Amélie
AU - Reis, André
AU - Arnesen, Thomas
AU - Thauvin-Robinet, Christel
AU - Zweier, Christiane
N1 - Publisher Copyright:
© 2016 The Authors.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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, whereas 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 identified three different novel and one known missense mutation in NAA10, de novo in 11 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 five 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.
AB - 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, whereas 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 identified three different novel and one known missense mutation in NAA10, de novo in 11 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 five 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.
KW - N-terminal acetylation
KW - NAA10
KW - X-linked
KW - intellectual disability
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U2 - 10.1002/humu.23001
DO - 10.1002/humu.23001
M3 - Article
C2 - 27094817
AN - SCOPUS:84978035610
SN - 1059-7794
VL - 37
SP - 755
EP - 764
JO - Human Mutation
JF - Human Mutation
IS - 8
ER -