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When the researchers discovered the gene, they partnered with collaborators and gave clinical diagnoses to 10 families who have relatives with neurodevelopmental disorders and intellectual disabilities.
"Our goal is to find as many of these genes required for brain function and take this knowledge back to patients and families to provide a clinically relevant genetic diagnosis," said Professor of Otorhinolaryngology-Head & Neck Surgery and Biochemistry & Molecular Biology at UMSOM Dr. Saima Riazuddin in a press release.
Dr. Riazuddin and her team worked together with several scientists in Pakistan to study a group of 350 families who were living in geographic isolation. This isolation resulted in inbreeding, leading to genetic disorders including neurodevelopmental disorders and intellectual disability.
From the group of 350, the team began focusing on one specific family that included two brothers and an uncle who showed symptoms of intellectual disability. These symptoms included delayed speech and other developmental milestones as well as epilepsy. Once Dr. Riazuddin and her team were able to identify the gene AP1G1, the gene was also detected in the 10 other families.
In order to determine the role the gene plays in development, researchers studied zebrafish without AP1G1. The zebrafish embryos without AP1G1 began to die off by the fourth day of the experiment. When researchers added back a mutated version of the genes, like what was found in the families showing signs of neurodevelopment disorders and intellectual disability, several symptoms were observed.
While some zebrafish embryos still died off, others saw major structural defects or minor tail deformities.
The AP1G1 gene contains the “blueprints” to create the protein Adaptor Protein 1 gamma 1 (AP1y1). This protein is one of the five parts that make the Adaptor Protein Complex. The Adaptor Protein Complex is responsible for building and transporting vesicles that move material around the cell.
"Think of these transport vesicles as little vehicles like trucks that have to load, transport, and unload their cargo around the cells (e.g. neurons) to provide the necessary supplies for the cell to function," Dr. Riazuddin explained.
The team manufactured normal and mutual versions of AP1G1 and put them in mammalian cells with cargo molecules. The cells that contained the mutated version of AP1G1 had vesicles that were delayed in their delivery and others that did not make their deliveries at all.
Researchers said these discoveries could help improve therapies in the future.
"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," E. Albert Reece, MD, PhD, MBA, executive vice president for Medical Affairs at UM Baltimore, and the John Z. and Akiko K. Bowers distinguished professor and dean at the University of Maryland School of Medicine said in the press release.
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