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Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15

Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15
Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15
N-alpha-acetylation is one of the most common co-translational protein modifications in humans and is essential for normal cell function. NAA10 encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. The auxiliary and regulatory subunits of the NatA complex are NAA15 and Huntington-interacting protein (HYPK), respectively. Through a genotype-first approach with exome sequencing, we identified and phenotypically characterized 30 individuals from 30 unrelated families with 17 different de novo or inherited, dominantly acting missense variants in NAA10 or NAA15. Clinical features of affected individuals include variable levels of intellectual disability, delayed speech and motor milestones and autism spectrum disorder. Additionally, some subjects present with mild craniofacial dysmorphology, congenital cardiac anomalies and seizures. One of the individuals is an 11-year-old boy with a frameshift variant in exon 7 of NAA10, who presents most notably with microphthalmia, which confirms a prior finding with a single family with Lenz microphthalmia syndrome. Biochemical analyses of variants as part of the human NatA complex, as well as enzymatic analyses with and without the HYPK regulatory subunit, help to explain some of the phenotypic differences seen among the different variants.
0964-6906
2900-2919
Cheng, Hanyin
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Gottlieb, Leah
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Marchi, Elaine
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Bhardwaj, Puja
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Rope, Alan F.
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Philippe, Christophe
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Eyaid, Wafaa
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Baralle, Diana
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Mancini, Grazia M.S.
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Conway, Simon J.
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Xia, Fan
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Baralle, Diana
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Mancini, Grazia M.S.
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Xia, Fan
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Marmorstein, Ronen
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Cheng, Hanyin, Gottlieb, Leah, Marchi, Elaine, Kleyner, Robert, Bhardwaj, Puja, Rope, Alan F., Rosenheck, Sarah, Moutton, Sébastien, Philippe, Christophe, Eyaid, Wafaa, Alkuraya, Fowzan S., Toribio, Janet, Mena, Rafael, Prada, Carlos E., Stessman, Holly, Bernier, Raphael, Wermuth, Marieke, Kauffmann, Birgit, Blaumeiser, Bettina, Kooy, R. Frank, Baralle, Diana, Mancini, Grazia M.S., Conway, Simon J., Xia, Fan, Chen, Zhao, Meng, Linyan, Mihajlovic, Ljubisa, Marmorstein, Ronen and Lyon, Gholson J. (2019) Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15. Human Molecular Genetics, 28 (17), 2900-2919. (doi:10.1093/hmg/ddz111).

Record type: Article

Abstract

N-alpha-acetylation is one of the most common co-translational protein modifications in humans and is essential for normal cell function. NAA10 encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. The auxiliary and regulatory subunits of the NatA complex are NAA15 and Huntington-interacting protein (HYPK), respectively. Through a genotype-first approach with exome sequencing, we identified and phenotypically characterized 30 individuals from 30 unrelated families with 17 different de novo or inherited, dominantly acting missense variants in NAA10 or NAA15. Clinical features of affected individuals include variable levels of intellectual disability, delayed speech and motor milestones and autism spectrum disorder. Additionally, some subjects present with mild craniofacial dysmorphology, congenital cardiac anomalies and seizures. One of the individuals is an 11-year-old boy with a frameshift variant in exon 7 of NAA10, who presents most notably with microphthalmia, which confirms a prior finding with a single family with Lenz microphthalmia syndrome. Biochemical analyses of variants as part of the human NatA complex, as well as enzymatic analyses with and without the HYPK regulatory subunit, help to explain some of the phenotypic differences seen among the different variants.

Text
NAA10_NAA15 HMG 2019 missense mutations_Final Published paper - Accepted Manuscript
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More information

Accepted/In Press date: 20 May 2019
e-pub ahead of print date: 25 May 2019
Published date: September 2019

Identifiers

Local EPrints ID: 433941
URI: http://eprints.soton.ac.uk/id/eprint/433941
ISSN: 0964-6906
PURE UUID: 1c018d64-f818-4e76-9430-eb40670efe9d
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 06 Sep 2019 16:30
Last modified: 26 Nov 2021 06:50

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Contributors

Author: Hanyin Cheng
Author: Leah Gottlieb
Author: Elaine Marchi
Author: Robert Kleyner
Author: Puja Bhardwaj
Author: Alan F. Rope
Author: Sarah Rosenheck
Author: Sébastien Moutton
Author: Christophe Philippe
Author: Wafaa Eyaid
Author: Fowzan S. Alkuraya
Author: Janet Toribio
Author: Rafael Mena
Author: Carlos E. Prada
Author: Holly Stessman
Author: Raphael Bernier
Author: Marieke Wermuth
Author: Birgit Kauffmann
Author: Bettina Blaumeiser
Author: R. Frank Kooy
Author: Diana Baralle ORCID iD
Author: Grazia M.S. Mancini
Author: Simon J. Conway
Author: Fan Xia
Author: Zhao Chen
Author: Linyan Meng
Author: Ljubisa Mihajlovic
Author: Ronen Marmorstein
Author: Gholson J. Lyon

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