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Type 1 interferons (IFN-1) are major signals activating the body's natural defenses against viruses, alerting cells and preparing them to defend themselves even before infection spreads. However, in some autoinflammatory diseases, inappropriate or excessive activation of this pathway contributes to immune system dysregulation, which can lead to collateral tissue damage, for example in the brain.
The “Neurogenetics and Neuroinflammation” laboratory, headed by Yanick Crow at Institut Imagine (Inserm, AP-HP, Université Paris Cité) recently identified rare “heterozygous” (only one of the two copies of the gene carries a mutation) mutations in the gene PTPN1 in 12 children. These children suffered a sudden and unexplained neurological decline associated with IFN-1 signal activation. They had no apparent impairment at birth, with their symptoms appearing progressively before the age of 10 years, leading to a rapid loss of motor and language functions. Cerebral atrophy (sometimes unilateral at onset) was the major feature on brain imaging, and all those tested had elevated concentrations of IFN-1 and neopterin, a marker of central nervous system inflammation, in their cerebrospinal fluid.
PTPN1 encodes the protein PTP1B (Protein Tyrosine Phosphatase 1B), which acts as a brake on IFN-1 signaling. When this brake is reduced, here by so-called “loss-of-function” mutations, IFN-1 signaling is significantly increased. In their study published in the journal The Lancet Neurology, researchers from Institut Imagine, the University of Edinburgh and their collaborators confirmed this mechanism by analyzing blood and skin cells from patients in the cohort, and by inactivating the PTPN1 gene in healthy cells using molecular scissors. These new results enlarge the spectrum of type I interferonopathies (genetic diseases involving an excess of IFN-1). As far as the management of brain inflammation is concerned, this work provides a strong incentive for doctors to include PTPN1 genetic testing as part of their routine clinical practice.
This work is an excellent example of the importance of non-targeted genetic analyses followed by targeted functional analyses for the diagnosis of complex rare diseases, here at the crossroads of neurology, immunology and genetics. Finally, this discovery suggests that the scientific community needs to be vigilant when it comes to the use of PTP1B inhibitors, drugs, that are currently being studied for the treatment of diabetes.
The study, published in March 2025, was conducted by PhD candidate Gaofeng Zhu, under the co-direction of Dr. Alice Lepelley at Institut Imagine. This work was made possible thanks to international collaborations involving geneticists, pediatricians and neurologists from a number of countries (Czech Republic, Germany, Italy, Slovenia, Great Britain and Israel). The study was funded by the French National Research Agency (ANR), the European Research Council (ERC), Institut Imagine and the University of Edinburgh.
Reference:
Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series.
G. Zhu et al., Lancet Neurol, 2025
doi: 10.1016/S1474-4422(24)00526-X