Transport system of essential materials in brain cells that is disturbed in certain genetic development disorders.

Photo credit: Dr. Riazuddin

Researchers at the University of Maryland School of Medicine (UMSOM) identified a new gene that could be linked to certain neurodevelopmental disorders and intellectual disabilities. Researchers believe that finding genes involved in certain types of developmental disorders is an important first step in determining the cause of those disorders and ultimately developing potential therapies to treat them. The paper was recently published in the. released American Journal of Human Genetics.

About 3 percent of the world’s population have an intellectual disability. Up to half of the cases are genetic. However, with many thousands of genes contributing to brain development, it was difficult to identify the specific cause for each patient.

After the researchers identified the gene, they worked with staff to provide clinical diagnoses to 10 other families around the world who had relatives with the condition. Researchers also used zebrafish to reveal the gene’s role in development and survival, demonstrating its importance in the proper functioning of the brain’s neurons.

“Our goal is to find as many of these genes that are necessary for brain function and to return this knowledge to patients and families for a clinically relevant genetic diagnosis,” says Saima Riazuddin, PhD, MPH, MBA, professor for Otorhinolaryngology-Head & Neck Surgery and Biochemistry & Molecular Biology at UMSOM.

Dr. Riazuddin and her team regularly work with several scientists in Pakistan to study a group of 350 geographically isolated families, which resulted in inbreeding that resulted in genetic disorders such as neurodevelopmental disorders and intellectual disabilities.

The team focused on a specific family of two brothers and an uncle with symptoms of intellectual disability, delayed speech and other developmental milestones and epilepsy. Other family members with similar symptoms had since died in childhood or early adulthood. Dr. Riazuddin and her team identified the AP1G1 gene as the culprit.

Then, working with 27 other institutions, her team was able to identify ten more families with the variations of the same gene that led to growth retardation and intellectual disability. These families lived in Italy, Germany, the Netherlands, Poland, and the United States.

To determine the role of the gene in development, the researchers constructed zebrafish without Ap1g1. These zebrafish embryos all began to die on the fourth day. When the researchers re-added mutated versions of the genes found in families with neurodevelopmental disorders and intellectual disabilities, they observed a spectrum of symptoms with some zebrafish embryos dying, some with large structural defects and others with only minor tail deformities.

The AP1G1 gene contains the blueprints to produce the protein adapter protein 1 gamma 1 (AP1γ1). This protein is one of five parts that make up the Adapter Protein Complex, which builds transport vesicles to move materials around cells.

“Think of these transport vesicles as small vehicles like trucks that have to load, transport and unload their cargo around the cells (eg neurons) in order to provide the necessary supply for the cell to function,” says Dr. Riazuddin.

Dr. Riazuddin produced normal and mutated versions of AP1G1, which they inserted into mammalian cells with cargo molecules marked in red. The cells with the mutated versions of AP1G1 had vesicles that delayed their freight or did not make their deliveries at all.

“Ultimately, improving the clinical diagnosis of these developmental disorders may offer new targets for therapies to one day treat these disorders and enable more people to live independently,” said E. Albert Reece, MD, PhD, MBA, executive vice president for Medical Affairs, UM Baltimore, and John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine.


This study was supported by the National Institute of Neurological Disorders and Stroke (R01NS107428), the EU FP7 Large-Scale Integrating Project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995), the Higher Education Commission of Pakistan (NRPU project 10700) and a Fondazione del . finances Monte grant (ID ROL: FDM / 4021).

The researchers have no conflicts of interest to explain.


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