Collaborative study identifies a novel microgliopathy in very young children

An international consorium, led by Prof Yanick Crow, Prof Colin Smith, Dr Jack Barrington and Dr Barry McColl (all University of Edinburgh) have identified a novel microgliopathy in very young children that that arises from mutations in the microglial-associated protein NRROSS (Negative Regulator of Reactive Oxygen Species)

Microglia are tissue-resident macrophages playing essential roles in central nervous system development and homeostasis. The importance of microglia for brain health in humans has been highlighted by the definition of Mendelian disorders associated with a disturbance of microglia-related protein function, the so-called microgliopathies. Now, an international consortium led by Yanick Crow, Colin Smith, Jack Barrington and Barry McColl, from the Institute of Genetics and Molecular Medicine (YC), the Centre for Clinical Brain Sciences (CS), the Centre for Discovery Brain Sciences and the UK Dementia Research Institute (JB, BMcC) in Edinburgh, describe a novel microgliopathy due to mutations in NRROSS.

In work partly funded by the RS Macdonald Charitable Trust (via an RS Macdonald Seedcorn Award from Edinburgh Neuroscience), they identified three patients demonstrating a highly stereotyped clinical and radiological phenotype comprising initially normal development, followed by the onset of epilepsy and a loss of skills in the second year of life, and then death by age 3 years. Study of the brain of one child demonstrated features consistent with a mouse model of NRROS deficiency, and transcriptomic analyses showed that brain expression of NRROS is highly localised to microglia in humans and mice.

These findings indicate that NRROS is indispensable in controlling the early development of a homeostatic microglial population and/or its ongoing preservation in the postnatal brain, thereby defining a loss of NRROS function as a novel microgliopathy in humans. They further implicate the role for correctly functioning microglia in normal brain development/maintenance, and suggest possible therapeutic targets for restoring microglial function.