The human genome contains more than 20,000 protein-coding genes, including NR4A2, which codes for an essential protein called NURR1. This protein has been extensively studied since the 1990s and we know from animal and cellular models that it plays a vital role in the development, maintenance and function of dopaminergic neurons in the brain. As a transcription factor, it has many other important functions, including the development of early neuronal circuits and brain networks that co-ordinate motor function. It also has very potent neuroprotective effects.

Dysregulation or depletion of NURR1, as a result of changes to upstream or downstream pathways, plays a contributory role in a number of neurodevelopmental conditions, such as ADHD, as well as many neurodegenerative conditions such as Parkinson’s Disease, Alzheimers and Multiple Sclerosis.

For our community, deficiency in NURR1 is the direct result of ultra rare genetic changes (micro deletions and variations) to the NR4A2 gene. In most cases, these are de novo changes, but they can also be inherited. Although there is still one functioning, healthy copy of the gene, one copy is compromised or entirely non-functional as a result of the genetic change. This results in reduced functionality and overall expression of NURR1 in the brain, and this is also known as haploinsufficiency.

A genetic deficiency of NURR1 is linked to a newly recognised neurodevelopmental disorder (NR4A2-related syndrome) but symptoms vary widely in onset, presentation and severity, including in members of the same family in inherited cases. They include significant issues and delays to language, learning and motor development and function, as well as various forms of epilepsy and wide-ranging neurological symptoms such as tics and tremors.

There are no targeted treatments or therapies currently available, but research using mouse models and on human cell lines (iPSCs) is being carried out at several research institutions to better understand the impact of genetic changes. CureNURR1 is sponsoring a cohort study at the University of Miami in Florida, USA and this will also explore treatment possibilities. There are several drug trials underway for small molecule therapeutics that have been shown to increase NURR1, and gene therapies may be developed in the future.