Newly acquired mutations in the NPTN gene can cause a rare developmental disorder characterised by autism and cognitive impairments. This is shown by an international study involving the LIN. The findings may help to genetically classify previously unexplained cases.
The research team studied eight children with developmental delays or impaired cognitive abilities. Seven of them had been diagnosed with autism. Some also developed epilepsy, lost previously acquired language skills, or exhibited abnormalities in movement and sleep.
In all eight children, the researchers found mutations in the same gene: NPTN. The parents did not carry these variants; they had arisen de novo in the children.
NPTN regulates calcium homeostasis in nerve cells
The NPTN gene contains the blueprint for the protein neuroplastin. This protein works in conjunction with calcium pumps in the cell membrane. PMCA pumps transport excess calcium out of the cell. Short-term increases in calcium concentration enable nerve cells to transmit and process signals. Afterwards, the concentration must fall again. If this process becomes unbalanced, nerve cells can no longer process signals reliably. The development of neural networks can also be impaired.
The NPTN variants investigated resulted in reduced levels of functional neuroplastin. Consequently, fewer active calcium pumps were available to the nerve cells.
Cell and animal models confirm the mechanism
To investigate how the genetic changes relate to the symptoms, the team analysed clinical and genetic data and carried out experiments using cell cultures, fruit flies and mice. In mice, a halving of neuroplastin levels was sufficient to significantly reduce the number of calcium pumps in the brain. The animals also exhibited changes in social behaviour. The experiments with fruit flies confirmed that several of the NPTN variants identified impair the function of neuroplastin.
“The strength of the study lies in the fact that we were able to link clinical observations directly to the underlying molecular mechanisms,” emphasises Dirk Montag from the LIN.
NPTN becomes relevant for genetic diagnosis
Until now, NPTN was considered only a possible candidate for neurodevelopmental disorders. The study results now published show that newly arising variants in this gene can cause a developmental disorder. Typical manifestations include autism and cognitive impairments of varying severity. For families whose children display similar symptoms, this knowledge can improve genetic diagnosis. In future, doctors will be able to incorporate NPTN more specifically into the interpretation of genetic findings.
To date, only eight affected children are known. Further cases and studies must therefore reveal the breadth of the clinical spectrum and whether treatment approaches can be derived from this in the long term.
Original publication:
Liang, Y. et al. (2026): De novo variants in NPTN cause a neurodevelopmental disorder with autism and neuroplastin-PMCA hypofunction. Genome Medicine 18, 93.
This study is open access.