Theune_TAGC2020.pdf (803.38 kB)

Using Zebrafish as a Model System for Studying the Autism Risk Gene ADNP

Download (803.38 kB)
posted on 20.04.2020, 22:27 by William C. Theune, Carter M. Takacs
Presentation of poster 2382C at TAGC 2020 Online. Files include a PDF of the poster (Theune_TAGC2020.pdf).

Autism Spectrum Disorders (ASD) are a classification of developmental disorders which are characterized by intellectual disability, difficulty with social interaction, and impairment in verbal and nonverbal communication. ASD affects as many as 1 in every 59 children worldwide and is an incredibly complex and genetically diverse group of disorders.
One of the most common forms of ASD is associated with de novo mutations in the adnp gene (Activity-dependent neuroprotector homeobox; accounting for 0.17% of ASD individuals). Termed ADNP syndrome, this disorder is characterized by intellectual disability, facial dysmorphia, and congenital heart defects. A clinical study of patients with ADNP syndrome found that frame-shift mutations in adnp lead to a loss of the C-terminus of the protein, believed to be responsible for recruiting components of the BAF chromatin remodeling complex.
We set out to use zebrafish as a model organism to gain mechanistic insights into ADNP function. Zebrafish have two paralogs of adnp; adnpa and adnpb. Our work suggests that ADNPA/B may play a role in cardiac, as well as, brain development. Specifically, CRISPR/Cas9-mediated knockout of adnpa leads to reduced blood flow and the development of cardiac edema at 48 hours-post fertilization(hpf). Approximately 24% of embryos within single clutches of adnpa F1 embryos exhibit this phenotype in addition to displaying a reduction in head size and severe deficiencies in motor function and sensory responses. Adnpb F0 embryos display a similar phenotype beginning at 24 hpf. At 6 days post-fertilization all affected embryos develop fatal hemorrhaging around the heart. These findings are consistent with the prevalence of cardiac deficits observed in patients with ADNP syndrome. Future work aims to determine the affected genetic regulatory pathways that underlie cardiac and neuronal phenotypes observed in the zebrafish mutant line.


Program Number