Newly identified genetic cause offers prospect of diagnosis for families affected by rare developmental disorders
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For some families, the reason why their child is not developing as expected remains unclear for a long time. Researchers at the Leibniz Institute for neurobiology (LIN) in Magdeburg have now identified a genetic cause of a previously unexplained developmental disorder. They showed that changes in the NPTN gene can impair the function of nerve cells. Affected children experience developmental delays, often autism and, in some cases, epilepsy. For families with similar unexplained conditions, the discovery could be an important step towards identifying a genetic cause. The study has now been published in the journal Genome Medicine.
Eight children, one common genetic cause
The international research team studied eight children for whom no clear cause of their developmental disorders had previously been identified. The researchers found changes in the NPTN gene in all eight children.
All of the children experienced developmental delays or intellectual disabilities. Seven had been diagnosed with autism. Some also developed epilepsy, lost previously acquired language skills or showed abnormalities in movement and sleep. In all eight children, the genetic changes had arisen spontaneously and had not been inherited from their parents.
Until now, NPTN had only been considered a candidate gene. Although researchers suspected a link with developmental disorders, they had not been able to demonstrate it. The new study provides evidence that changes in this gene can contribute to neurodevelopmental disorders and autism.
“Our findings show that neuroplastin plays an important role in the brain. If the protein is altered or if the body does not produce enough of it, nerve cells may no longer be able to process signals correctly,” says PD Dr Dirk Montag of the LIN.
How changes in the NPTN gene disrupt brain development
The NPTN gene contains the instructions for producing the protein neuroplastin. This protein helps nerve cells regulate their calcium balance. Calcium is essential for communication between nerve cells because it allows them to transmit and process signals.
The researchers showed that altered neuroplastin cannot perform this function reliably. As a result, certain calcium pumps known as PMCA pumps function less effectively. These pumps remove excess calcium from cells. If calcium remains active for longer than usual, it can disrupt signal processing in nerve cells and impair the development of neural networks.
Cell and animal models confirm the link
To understand the effects of the genetic changes, the researchers combined genetic analyses with experiments using cell cultures and animal models. They observed markedly altered calcium signals in nerve cells. In mice, reducing the amount of neuroplastin by half led to a substantial decline in important calcium pumps in the brain. In some cases, their levels fell by almost 50 per cent. Mice with lower neuroplastin levels also showed less interest in social interaction. Experiments with fruit flies provided further evidence that changes in neuroplastin impair the protein’s function.
“The strength of this study lies in establishing a direct link between the clinical observations and the underlying molecular mechanisms,” says Dirk Montag.
New insights for diagnosis and research
The results provide a foundation for identifying similar cases in the future. For affected families, knowing the genetic cause can be an important step towards a definitive diagnosis and a better assessment of how the condition may develop.
The discovery also opens up new avenues for research. The researchers are now investigating whether the disrupted calcium signalling pathways can be influenced and at what stage an intervention might be effective.
Further research is needed, as only eight affected children have been identified to date. Nevertheless, the study provides an important starting point for gaining a better understanding of rare developmental disorders and their causes.
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