ANK3, which encodes multiple isoforms of ankyrin-G, is crucial for neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms with different domains and distinct expression patterns. It is involved in various neural-related pathways, and its function is of great significance in the nervous system [2]. Animal models, especially mouse models, have been used to study ANK3's role in related biological processes [3,4].

ANK3 variants are associated with multiple neurodevelopmental phenotypes. Heterozygous missense variants in ANK3 have been linked to autism spectrum disorder, while more severe phenotypes are caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants [1]. In a study of 27 individuals with mono-or biallelic ANK3 variants, common features included language delay, intellectual disability, hypotonia, and epilepsy, with biallelic variants leading to a more severe phenotype [2]. In an Ank3 mouse model of epilepsy-bipolar disorder comorbidity, deletion of Ank3-1b led to absence epilepsy, abnormal sleep, hyperactivity, and repetitive behaviors, along with neocortical oscillation disturbances [3]. A mouse model with a missense p.W1989R mutation in Ank3 showed reduced inhibitory signaling in the somatosensory cortex and increased pyramidal cell excitability, similar to human BD symptoms, which could be normalized by lithium treatment [4].

In conclusion, ANK3 is essential for neuronal development and signaling. Studies using gene-knockout or mutant mouse models have revealed its role in neurodevelopmental disorders, epilepsy-bipolar disorder comorbidity, and related neural functions. Understanding ANK3's function through these models provides insights into the mechanisms of these diseases and potential therapeutic directions.

References:

1. Kloth, Katja, Lozic, Bernarda, Tagoe, Julia, Bijlsma, Emilia K, Lessel, Davor. 2021. ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants. In Neurogenetics, 22, 263-269. doi:10.1007/s10048-021-00655-4. https://pubmed.ncbi.nlm.nih.gov/34218362/

2. Furia, Francesca, Levy, Amanda M, Theunis, Miel, Gardella, Elena, Tümer, Zeynep. 2024. The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants. In Clinical genetics, 106, 574-584. doi:10.1111/cge.14587. https://pubmed.ncbi.nlm.nih.gov/38988293/

3. Villacres, Juan E, Riveira, Nicholas, Kim, Sohmee, Noebels, Jeffrey L, Lopez, Angel Y. 2023. Abnormal patterns of sleep and waking behaviors are accompanied by neocortical oscillation disturbances in an Ank3 mouse model of epilepsy-bipolar disorder comorbidity. In Translational psychiatry, 13, 403. doi:10.1038/s41398-023-02700-2. https://pubmed.ncbi.nlm.nih.gov/38123552/

4. Caballero-Florán, René N, Nelson, Andrew D, Min, Lia, Jenkins, Paul M. 2023. Effects of chronic lithium treatment on neuronal excitability and GABAergic transmission in an Ank3 mutant mouse model. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.10.26.564203. https://pubmed.ncbi.nlm.nih.gov/37961630/