Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
27
10
2022
accepted:
17
04
2023
revised:
11
02
2023
medline:
10
7
2023
pubmed:
3
5
2023
entrez:
2
5
2023
Statut:
ppublish
Résumé
Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation in NAA10 and NAA15 in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals with NAA10 variants and 19 individuals with NAA15 variants, which were added to all known cases (N = 106 for NAA10 and N = 66 for NAA15). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands with NAA10 variants is significantly lower than the probands with NAA15 variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with an NAA15 frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end of NAA10 have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.
Identifiants
pubmed: 37130971
doi: 10.1038/s41431-023-01368-y
pii: 10.1038/s41431-023-01368-y
pmc: PMC10325952
doi:
Substances chimiques
N-Terminal Acetyltransferase E
EC 2.3.1.258
N-Terminal Acetyltransferase A
EC 2.3.1.254
NAA15 protein, human
0
NAA10 protein, human
EC 2.3.1.255
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
824-833Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM060293
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133408
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118090
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM071339
Pays : United States
Informations de copyright
© 2023. The Author(s).
Références
Arnesen T, Van Damme P, Polevoda B, Helsens K, Evjenth R, Colaert N, et al. Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. Proc Natl Acad Sci USA. 2009;106:8157–62.
doi: 10.1073/pnas.0901931106
pubmed: 19420222
pmcid: 2688859
Starheim KK, Gevaert K, Arnesen T. Protein N-terminal acetyltransferases: when the start matters. Trends Biochem Sci. 2012;37:152–61.
doi: 10.1016/j.tibs.2012.02.003
pubmed: 22405572
Arnesen T, Anderson D, Baldersheim C, Lanotte M, Varhaug JE, Lillehaug JR. Identification and characterization of the human ARD1-NATH protein acetyltransferase complex. Biochem J. 2005;386:433–43.
doi: 10.1042/BJ20041071
pubmed: 15496142
pmcid: 1134861
Arnesen T, Starheim KK, Van Damme P, Evjenth R, Dinh H, Betts MJ, et al. The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation. Mol Cell Biol. 2010;30:1898–909.
doi: 10.1128/MCB.01199-09
pubmed: 20154145
pmcid: 2849469
Gottlieb L, Marmorstein R. Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK. Structure 2018;26:925–35.e8.
doi: 10.1016/j.str.2018.04.003
pubmed: 29754825
pmcid: 6031454
Feng J, Li R, Yu J, Ma S, Wu C, Li Y, et al. Protein N-terminal acetylation is required for embryogenesis in Arabidopsis. J Exp Bot. 2016;67:4779–89.
doi: 10.1093/jxb/erw257
pubmed: 27385766
pmcid: 4973746
Chen D, Zhang J, Minnerly J, Kaul T, Riddle DL, Jia K. daf-31 encodes the catalytic subunit of N alpha-acetyltransferase that regulates Caenorhabditis elegans development, metabolism and adult lifespan. PLoS Genet. 2014;10:e1004699.
doi: 10.1371/journal.pgen.1004699
pubmed: 25330189
pmcid: 4199510
Ree R, Myklebust LM, Thiel P, Foyn H, Fladmark KE, Arnesen T. The N-terminal acetyltransferase Naa10 is essential for zebrafish development. Biosci Rep [Internet]. 2015;35. https://doi.org/10.1042/BSR20150168
Dörfel MJ, Lyon GJ. The biological functions of Naa10 - from amino-terminal acetylation to human disease. Gene 2015;567:103–31.
doi: 10.1016/j.gene.2015.04.085
pubmed: 25987439
pmcid: 4461483
Aksnes H, Ree R, Arnesen T. Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases. Mol Cell. 2019;73:1097–114.
doi: 10.1016/j.molcel.2019.02.007
pubmed: 30878283
pmcid: 6962057
Kweon HY, Lee M-N, Dorfel M, Seo S, Gottlieb L, PaPazyan T, et al. Naa12 compensates for Naa10 in mice in the amino-terminal acetylation pathway. Elife [Internet]. 2021 Aug 6;10. https://doi.org/10.7554/eLife.65952
Blomen VA, Májek P, Jae LT, Bigenzahn JW, Nieuwenhuis J, Staring J, et al. Gene essentiality and synthetic lethality in haploid human cells. Science 2015;350:1092–6.
doi: 10.1126/science.aac7557
pubmed: 26472760
Wang T, Birsoy K, Hughes NW, Krupczak KM, Post Y, Wei JJ, et al. Identification and characterization of essential genes in the human genome. Science 2015;350:1096–101.
doi: 10.1126/science.aac7041
pubmed: 26472758
pmcid: 4662922
Rope AF, Wang K, Evjenth R, Xing J, Johnston JJ, Swensen JJ, et al. Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. Am J Hum Genet. 2011;89:28–43.
doi: 10.1016/j.ajhg.2011.05.017
pubmed: 21700266
pmcid: 3135802
Lyon GJ. Personal account of the discovery of a new disease using next-generation sequencing. Interview by Natalie Harrison. Pharmacogenomics 2011;12:1519–23.
doi: 10.2217/pgs.11.117
pubmed: 22044413
Gogoll L, Steindl K, Joset P, Zweier M, Baumer A, Gerth-Kahlert C, et al. Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature. Am J Med Genet A. 2021;185:2546–60.
doi: 10.1002/ajmg.a.62351
pubmed: 34075687
pmcid: 8361982
Van Damme P, Støve SI, Glomnes N, Gevaert K, Arnesen T. A Saccharomyces cerevisiae model reveals in vivo functional impairment of the Ogden syndrome N-terminal acetyltransferase NAA10 Ser37Pro mutant. Mol Cell Proteom. 2014;13:2031–41.
doi: 10.1074/mcp.M113.035402
Dörfel MJ, Fang H, Crain J, Klingener M, Weiser J, Lyon GJ. Proteomic and genomic characterization of a yeast model for Ogden syndrome. Yeast 2017;34:19–37.
doi: 10.1002/yea.3211
pubmed: 27668839
Myklebust LM, Van Damme P, Stove SI, Dörfel MJ, Abboud A, Kalvik TV, et al. Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects. Hum Mol Genet. 2015;24:1956–76.
doi: 10.1093/hmg/ddu611
pubmed: 25489052
Bader I, McTiernan N, Darbakk C, Boltshauser E, Ree R, Ebner S, et al. Severe syndromic ID and skewed X-inactivation in a girl with NAA10 dysfunction and a novel heterozygous de novo NAA10 p.(His16Pro) variant - a case report. BMC Med Genet. 2020;21:153.
doi: 10.1186/s12881-020-01091-1
pubmed: 32698785
pmcid: 7374887
Cheng H, Gottlieb L, Marchi E, Kleyner R, Bhardwaj P, Rope AF, et al. Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15. Hum Mol Genet [Internet]. 2019 May 25; https://doi.org/10.1093/hmg/ddz111
McTiernan N, Gill H, Prada CE, Pachajoa H, Lores J, CAUSES study. et al. NAA10 p.(N101K) disrupts N-terminal acetyltransferase complex NatA and is associated with developmental delay and hemihypertrophy. Eur J Hum Genet. 2021;29:280–8.
doi: 10.1038/s41431-020-00728-2
pubmed: 32973342
Ree R, Geithus AS, Tørring PM, Sørensen KP, Damkjær M, DDD study. et al. A novel NAA10 p.(R83H) variant with impaired acetyltransferase activity identified in two boys with ID and microcephaly. BMC Med Genet. 2019;20:101.
doi: 10.1186/s12881-019-0803-1
pubmed: 31174490
pmcid: 6554967
Støve SI, Blenski M, Stray-Pedersen A, Wierenga KJ, Jhangiani SN, Akdemir ZC, et al. A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy. Eur J Hum Genet. 2018;26:1294–305.
doi: 10.1038/s41431-018-0136-0
pubmed: 29748569
pmcid: 6117304
Afrin A, Prokop JW, Underwood A, Uhl KL, VanSickle EA, Baruwal R, et al. NAA10 variant in 38-week-gestation male patient: a case study. Cold Spring Harb Mol Case Stud [Internet]. 2020;6. https://doi.org/10.1101/mcs.a005868
Johnston JJ, Williamson KA, Chou CM, Sapp JC, Ansari M, Chapman HM, et al. NAA10 polyadenylation signal variants cause syndromic microphthalmia. J Med Genet. 2019;56:444–52.
doi: 10.1136/jmedgenet-2018-105836
pubmed: 30842225
Gupta AS, Saif HA, Lent JM, Couser NL. Ocular Manifestations of the NAA10-Related Syndrome. Case Rep Genet. 2019;2019:8492965.
pubmed: 31093388
pmcid: 6476065
Maini I, Caraffi SG, Peluso F, Valeri L, Nicoli D, Laurie S, et al. Clinical Manifestations in a Girl with NAA10-Related Syndrome and Genotype–Phenotype Correlation in Females. Genes 2021;12:900.
doi: 10.3390/genes12060900
pubmed: 34200686
pmcid: 8230408
Cheng H, Dharmadhikari AV, Varland S, Ma N, Domingo D, Kleyner R, et al. Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies. Am J Hum Genet. 2018;102:985–94.
doi: 10.1016/j.ajhg.2018.03.004
pubmed: 29656860
pmcid: 5986698
Ward T, Tai W, Morton S, Impens F, Van Damme P, Van Haver D, et al. Mechanisms of congenital heart disease caused by NAA15 haploinsufficiency. Circ Res. 2021;128:1156–69.
doi: 10.1161/CIRCRESAHA.120.316966
pubmed: 33557580
pmcid: 8048381
Hsieh T-C, Bar-Haim A, Moosa S, Ehmke N, Gripp KW, Pantel JT, et al. GestaltMatcher facilitates rare disease matching using facial phenotype descriptors. Nat Genet [Internet]. 2022 Feb 10; https://doi.org/10.1038/s41588-021-01010-x
Hustinx A, Hellmann F, Sümer Ö, Javanmardi B, André E, Krawitz P, et al. Improving Deep Facial Phenotyping for Ultra-rare Disorder Verification Using Model Ensembles. In: Proceedings of the IEEE/CVF Winter Conference on Applications of Computer Vision (WACV). 2023:5018–28.
Dingemans AJM, Stremmelaar DE, Vissers LELM, Jansen S, Nabais Sá MJ, van Remortele A, et al. Human disease genes website series: An international, open and dynamic library for up-to-date clinical information. Am J Med Genet A. 2021;185:1039–46.
doi: 10.1002/ajmg.a.62057
pubmed: 33439542
pmcid: 7986414
Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46:D1062–7.
doi: 10.1093/nar/gkx1153
pubmed: 29165669
Chaudhary P, Ha E, Vo TTL, Seo JH. Diverse roles of arrest defective 1 in cancer development. Arch Pharm Res. 2019;42:1040–51.
doi: 10.1007/s12272-019-01195-0
pubmed: 31813105
Sandomirsky K, Marchi E, Gavin M, Amble K, Lyon GJ. Phenotypic variability and Gastrointestinal Manifestations/Interventions for growth in Ogden syndrome (also known as NAA10-related Syndrome) [Internet]. medRxiv. 2022. http://medrxiv.org/lookup/doi/10.1101/2022.03.16.22272517
Casey JP, Støve SI, McGorrian C, Galvin J, Blenski M, Dunne A, et al. NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment. Sci Rep. 2015;5:16022.
doi: 10.1038/srep16022
pubmed: 26522270
pmcid: 4629191
Lee C-C, Shih Y-C, Kang M-L, Chang Y-C, Chuang L-M, Devaraj R, et al. Naa10p inhibits beige adipocyte-mediated thermogenesis through N-α-acetylation of Pgc1α. Mol Cell. 2019;76:500–15.e8.
doi: 10.1016/j.molcel.2019.07.026
pubmed: 31422874
Chokron S, Kovarski K, Dutton GN. Cortical Visual Impairments and Learning Disabilities. Front Hum Neurosci. 2021;15:713316.
doi: 10.3389/fnhum.2021.713316
pubmed: 34720906
pmcid: 8548846
Shishido A, Morisada N, Tominaga K, Uemura H, Haruna A, Hanafusa H, et al. A Japanese boy with NAA10-related syndrome and hypertrophic cardiomyopathy. Hum Genome Var. 2020;7:23.
doi: 10.1038/s41439-020-00110-0
pubmed: 32864149
pmcid: 7429835
Lyon GJ, Vedaie M, Besheim T, Park A, Marchi E, Gottlieb L, et al. Expanding the Phenotypic spectrum of Ogden syndrome (NAA10-related neurodevelopmental syndrome) and NAA15-related neurodevelopmental syndrome [Internet]. medRxiv. 2022. http://medrxiv.org/content/early/2022/08/23/2022.08.22.22279061.abstract
McTiernan N, Tranebjærg L, Bjørheim AS, Hogue JS, Wilson WG, Schmidt B, et al. Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N-terminal acetylation. Hum Genet [Internet]. 2022 Jan 17; https://doi.org/10.1007/s00439-021-02427-4
Saunier C, Stove SI, Popp B, Gerard B, Blenski M, AhMew N, et al. Expanding the Phenotype Associated with NAA10-Related N-Terminal Acetylation Deficiency. Hum Mutat. 2016;37:755–64.
doi: 10.1002/humu.23001
pubmed: 27094817
pmcid: 5084832
Magin RS, Deng S, Zhang H, Cooperman B, Marmorstein R. Probing the interaction between NatA and the ribosome for co-translational protein acetylation. PLoS ONE. 2017;12:e0186278.
doi: 10.1371/journal.pone.0186278
pubmed: 29016658
pmcid: 5634638
Lyon GJ, O’Rawe J. Human genetics and clinical aspects of neurodevelopmental disorders. In: Mitchell K, editor. The Genetics of Neurodevelopmental Disorders. Hoboken, New Jersey, U.S.: Wiley; 2015.
Esmailpour T, Riazifar H, Liu L, Donkervoort S, Huang VH, Madaan S, et al. A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome. J Med Genet. 2014;51:185–96.
doi: 10.1136/jmedgenet-2013-101660
pubmed: 24431331
Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, et al. A dyadic approach to the delineation of diagnostic entities in clinical genomics. Am J Hum Genet. 2021;108:8–15.
doi: 10.1016/j.ajhg.2020.11.013
pubmed: 33417889
pmcid: 7820621