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Impact Case Study

Loss of cellular ‘caretakers’ causes fatal infant brain disorder

A rare genetic mutation undermines brain development and function by blocking brain cell communication.

19 June 2018

The discovery of a genetic defect that causes a rare lethal infant development disorder has helped reveal the importance of a key protein for brain functioning. 

Ubiquitin helps regulate the activities of other proteins, and is found in almost all human cells. It contributes to brain development and function, but the mechanisms involved are unclear. It is widely considered that ubiquitin does this by tagging unneeded or damaged proteins to be broken up by protein complexes called proteasomes. 

An international team of researchers based in the UK, Ireland and Saudi Arabia worked with infants from four families suffering seizures and a range of similar severe developmental problems, including impaired brain growth, deterioration of muscle control, and optic nerve degeneration. 

DNA sequencing showed the patients had almost identical mutations in a gene that encodes the ubiquitin-binding protein phospholipase A2-activating protein (PLAA). 

The researchers, led by Emma Hall, and Pleasantine Mill, at the MRC Human Genetics Unit at the University of Edinburgh, named the condition PLAA-associated neurodevelopmental disorder (PLAAND). 

“It’s a rare but deeply troubling condition,” says Mill. “These kids don’t meet developmental milestones, and they die by the age of six. 

The team used the CRISPR-Cas9 genome editing technique to engineer mice with identical mutations to the children. A series of physiological, cellular and molecular tests were carried out to better understand the physiological and molecular consequences. 

Cells can internalise material on their surfaces to be broken down or recycled by engulfing them in an area of their outer membranes that bud off into an internal compartment through a process called endocytosis. 

Rather than ubiquitin just tagging proteins to be broken down by proteasomes as previously thought, Mill’s group found it to be crucial to endocytosis at synapses, where signals are passed between brain cells. They believe PLAA plays a crucial role in brain cell function by reading ubiquitin tags attached to other proteins to determine whether they should be internalised for destruction, recycled or returned to the cell surface. 

Mutations to the PLAA gene reduce the quantity and stability of its protein product. This undermines the ability of brain cells to communicate and to clear away damaged or superfluous proteins, causing malfunctions and disease. 

“Ubiquitin signalling plays a key role in how synapses talk to each other during brain development and function, and mutations can have devastating effects on child health,” says Mill. 

The discovery could provide molecular targets for future therapeutic interventions.


  1. Hall, E. A., Nahorski, M. S., Murray, L. M., Shaheen, R., & Mill, P. PLAA mutations cause a lethal infantile epileptic encephalopathy by disrupting ubiquitin-mediated endolysosomal degradation of synaptic proteins. The American Journal of Human Genetics 100, 706–724 (2017). | article