A Yeast Model for Genetic Variants in Human NAA15 associated with Autism Spectrum Disorder

According to WHO 1 in 160 children has an Autism Spectrum Disorder (ASD), which is a neurodevelopmental disorder manifesting in a range of symptoms such as impaired social skills, repetitive behaviors, and restricted interests. There is a broad consensus that ASD has a strong hereditary component and extensive research efforts have been undertaken to identify genetic risk factors of ASD. We have identified and phenotypically characterized 37 individuals from 32 unrelated families with 25 different and likely gene disruption variants in NAA15, which is emerging as a high impact ASD gene. All subjects have variable degrees of neurodevelopmental disabilities, including intellectual disability, delayed speech and motor milestones, and ASD. In most cases the mutation occurred de novo, while familial inheritance was observed in three families. The NAA15 gene encodes the auxiliary subunit of a protein complex called NatA, which N-terminally acetylates proteins while they are being synthesized. To gain an insight into the genotype to phenotype relationships in ASD we turned to the budding yeast Saccharomyces cerevisiae. Functional assays in yeast confirmed a deleterious effect for two of the truncating variants in NAA15. We propose that defects in NatA-mediated protein N-terminal acetylation lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of NatA activity in normal human development. This work gives new insight into the heredity of ASD and may lead to better treatment of patients with neurodegenerative disorders.