Novel neurodevelopmental disorder risk gene identified
A team, composed of researchers from McMaster University, the University of Toronto in Canada, and the University Medical Center Hamburg-Eppendorf in Germany, has demonstrated that a gene called TAOK2
may contribute to the development of neurodevelopmental disorders such as autism.
Neurodevelopmental disorders (NDDs) are a group of diseases associated with impairments of the growth and development of the brain or central nervous system. These diseases generally affect brain functions such as emotion, learning ability, self-control and memory. The etiology of NDDs is complex. Many factors can contribute to the development of NDDs, including deprivation from social and emotional care, genetic abnormalities, various diseases, infections, nutritional factors, injuries, and toxic and environmental factors.
Many forms of NDDs are resulting from the so-called microdeletion, which refers to a relatively small loss of the portion of the chromosome that includes several genes. For example, microdeletions on chromosome 16p11.2 have been associated with one of the most common NDD forms, autism spectrum disorder (ASD). The TAOK2 gene is located in this ASD-associated 16p11.2 chromosomal deletion region. Some studies have suggested a possible link between TAOK2 and NDDs. However, more studies are still needed to investigate whether genetic alterations in TAOK2 contribute to NDDs.
In this work, the team used genetically engineered mice to study the role of TAOK2 in neural circuit development. Behavioral analysis of TAOK2 heterozygous (Het) and knockout (KO) mice revealed gene dosage-dependent impairments in cognition, anxiety, and social interaction. Additionally, the team identified new missense and truncating loss-of-function mutations in the TAOK2 gene in ASD patients, using whole-genome sequencing. These mutations in TAOK2 were found to differentially impair TAOK2 function and dendrite and synaptic development. Further experiments demonstrated that loss of TAOK2 activity leads to a reduction in RhoA activation, while pharmacological enhancement of RhoA activity rescues synaptic defects.
These results suggest TAOK2 as a risk gene for NDDs and identify RhoA signaling as a mediator of TAOK2-dependent synaptic development. To better understand TAOK2's role in NDDs, it's needed to determine whether other ASD or NDD patients also have pathogenic variations in TAOK2.
The full paper, titled "Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling," can be read in the journal Molecular Psychiatry.
In the future research, the team plans to "screen candidate drugs that correct the cognitive brain deficits caused by genetic mutations in TAOK2," according to co-senior author Dr. Karun Singh, who is principal investigator at the Stem Cell and Cancer Research Institute of McMaster University and whose primary research objective is to understand the pathological mechanisms of ASD and other NDDs.
NDDs represent a major medical problem in the world, and treatment options are limited. The lack of a comprehensive understanding of the pathogenic mechanisms of NDDs has hindered the development of novel therapies. Genetic studies have suggested that there is a genetic basis for many forms of NDDs, but more research is still needed to identify genetic factors that increase NDD risk. Moreover, there is a lack of model organisms that can faithfully recapitulate the genetic diversity and heterogeneity of NDDs. All these facts increase the difficulties in studying NDDs.