Researchers have discovered that the gene AP1G1 could be associated with certain neurodevelopmental disorders and intellectual disabilities.
A person with an intellectual disability is an individual who experiences certain limitations in terms of cognitive functioning. It is estimated that 3% of the global population has an intellectual disability, with the detected prevalence rising due to (1) an ageing population, (2) the rapid spread of chronic diseases, and (3) improvements in emerging technologies that can be used to measure disabilities.
Up to half of neurodevelopmental disorders are caused by genetic conditions; for example, Down syndrome, Fragile X syndrome and phenylketonuria. However, it is extremely difficult to identify the specific cause of a genetic-related disability – a huge number of genes contribute to each person’s unique brain development. Nonetheless, researchers from the University of Maryland School of Medicine (UMSOM) have recently identified a new gene that is believed to be linked to certain intellectual disabilities and neurodevelopmental disorders.
The AP1G1 gene
Adaptor protein (AP) complexes mediate intracellular membrane trafficking along endocytic and secretory transport pathways. They play important roles in maintaining the normal physiological function of eukaryotic cells. Therefore, it is unsurprising that the dysfunction of AP complexes is associated with several heritable human disorders, including intellectual disabilities.
Five AP complexes have been identified to date, one of which is called AP-1. A sub-unit of this complex is named Adaptor Protein 1 gamma 1 (AP1γ1). This protein is encoded for by the AP1G1 gene.
The researchers at UMSOM studied 11 families from different ethnicities, and found that variants in AP1G1 were linked to neurodevelopmental disorders, including severe intellectual disability and epilepsy. Investigations within mammalian cells showed that mutant variations of the AP1G1 gene did not carry out its transport and cargo functions correctly. In silico analysis and 3D protein modelling simulations predicted that this was due to the AP1γ1 protein becoming altered when it folded for missense variants.
To explore the role played by AP1G1 in the normal function of brain neurons, zebrafish were engineered without the gene. It was found that knocking out AP1G1 led to severe morphological defects and sometimes death. This provided evidence for the importance of AP1G1, and in turn AP1γ1, in development.
Discovering genes causing intellectual disabilities
The study provided evidence for variations in the AP1G1 gene being associated with neurodevelopmental disorders in diverse populations. Discovering the genes involved in certain types of intellectual disabilities provides the important first step in determining the cause of the disorder. “Our goal is to find as many of these genes required for brain function as possible. And take this knowledge back to patients and families to provide a clinically relevant genetic diagnosis,” Professor Saima Riazuddin, from UMSOM, explained.
Further exploration into the mechanisms behind the variant sub-units, such as AP1γ1, will ultimately aid the development of potential therapies for treating these conditions. Dr Albert Reece, dean of UMSOM, explained: “Improving clinical diagnosis of these developmental disorders may eventually provide new targets for therapies, in order to, one day, be able to treat these conditions allowing more people to live independently.”
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