A de novo loss-of-function (LoF) variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Furthermore, analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified NAA15 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. Three novel de novo LoF variants in NAA15 were identified in probands reported to have a formal diagnosis of ASD in the Supplementary Material from Stessman et al., 2017 (PMID 28191889). An additional de novo LoF variant in NAA15 was identified in an ASD proband from a multiplex family by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017 (PMID 28263302). Phenotypic characterization of 38 individuals from 33 unrelated families with de novo or inherited loss-of-function variants in NAA15, many of whom were previously unreported, identified recurrent phenotypes, including intellectual disability (23/23 cases, 100%), speech delay (32/33 cases, 97%), motor delay and related abnormalities (31/32 cases, 97%), ASD, ADHD, or behavioral issues (30/33 cases, 91%), and mild dysmorphic features (18/28 cases, 64%). Two additional de novo loss-of-function variants in the NAA15 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified NAA15 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
Auxillary subunit of the N-terminal acetyltransferase A (NatA) complex which displays alpha (N-terminal) acetyltransferase activity. The NAT activity may be important for vascular, hematopoietic and neuronal growth and development.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism.
Naa15 Haploinsufficiency and De Novo Missense Variants Associate With Neurodevelopmental Disorders and Interfere With Neurogenesis and Neuron Development
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Unveiling Hidden Genetic Architectures: Molecular Diagnostic Yield of Whole Exome Sequencing in 50 Children With Autism Spectrum Disorder Negative for Copy Number Variations
The homozygous Naa15 knockout shows embryonic lethality, while the heterozygous model of haploinsufficiency shows typical survival, with a 50% reduction of Naa15 protein levels. The heterozygous model shows increased repetitive digging, increased locomotor activity in the open field test, and increased anxiety-like behavior in the elevated plus maze. The model does not show changes in sociability or brain size. The heterozygote does show changes in cortical lamination, while a Naa15 knockdown model shows increased neural precursor proliferation and radial glial number.
References
Type
Title
Author, Year
Primary
Naa15 Haploinsufficiency and De Novo Missense Variants Associate With Neurodevelopmental Disorders and Interfere With Neurogenesis and Neuron Development
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Deletion of exons 2-6 (~10kb) was targeted with CRISPR/Cas9 technology, which introduced a frameshift mutation and consequently, the loss of protein function.
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: NanJing Biomedical Research Institute
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Deletion of exons 2-6 (~10kb) was targeted with CRISPR/Cas9 technology, which introduced a frameshift mutation and consequently, the loss of protein function.
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: NanJing Biomedical Research Institute
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
shRNA sequences specific to the mouse Naa15 gene were inserted into the pFUGW-H1-GFP vector for in utero electroporation. Plasmids (2ug/uL) were injected into the embryonic brain ventricle. The plasmid mixture was then electroporated from the ventricle to the neural progenitor cells.
Allele Type: Knockdown
Strain of Origin: Not applicable
Genetic Background: Not specified
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Xiangbin Jia (Central South University, Hunan, China)
