Rett syndrome (RTT) is a rare neurodevelopmental disease. Mutations in MECP2 (located on the X chromosome) are the most common cause. However, mutations in other genes such as CDKL5 and FOXG1 have been reported to produce a Rett-like phenotype. How these different genetic defects determine similar clinical features has yet to be elucidated. Italian researchers from University of Siena, in collaboration with the Yale University School of Medicine in New Haven, tried to find a unique explanation for these three apparently different anomalies.


Patients affected by RTT experience numerous symptoms including movement and language problems, autism-like features, and often epilepsy. It is a genetic but often not a hereditary disorder, which implies that mutations can occur randomly and prenatal diagnosis through the analysis of the familiar medical history is not the answer. In fact, the risk for a family with a child suffering from RTT to have another child with the same disease is less than 1%. As already mentioned, the most recurrent mutations are found on the genes encoding for MECP2, which is necessary for neuron function and maintenance of neuronal connections. CDKL5 is also essential for normal brain activities. Both genes can regulate the activity of many other genes. Mutations associated with an earlier onset of RTT, also called congenital RTT, has been identified on the gene encoding for FOXG1. FOXG1 is a protein widely expressed in the forebrain, in particular in the telencephalon, the embryonic structure that will give rise to cerebrum.


The authors started from already published data showing that in patients carrying a mutation in MECP2 or CDKL5 genes there was an increase in the expression of the glutamate dehydrogenase I (GluD1), factor involved in the formation of inhibitory GABAergic synapses and in the survival of the inhibitory interneurons. In addition, high levels of GluD1 were reported in cases of schizophrenia and autism. Thus, the researchers suspected that RTT’s phenotype might be related to an impaired balance between stimulatory and inhibitory signals that may affect neuron function or synapsis formation.


To figure out the role of GluD1 in patients with mutated FOXG1, they obtained induced pluripotent stem cell (iPSCs) from two patients. IPSCs can be generated by introducing four “reprogramming” genes in adult cells. This technique was developed by Shinya Yamanaka and John Gordon, winners of the Nobel Prize in Medicine for this discovery in 2002. One of the main advantage of this method is that iPSCs can be propagate indefinitely and give rise to other types of cells. In this case, IPSCs from patients with mutations in FOXG1 were further differentiated to neurons, especially to glutamatergic cells. The increase of GluD1 was confirmed also in the neurons obtained by iPSCs from patients, as well as an increase in other pre-synaptic and post-synaptic inhibitory proteins, like GAD67 and GABAA receptor subunit α1. By contrast, the expression of excitatory molecules, such as the glutamate transporters VGLUT1 and VGLUT2, was reduced.


Similarly, fetal brain from foxg1 deficient mice also presented more Glud1, GAD67 and GABAA receptor subunit α1protein levels than normal mice. This results indicated that neuron cells obtained from patients’ iPSCs, phenotypically closer to embryonic neuronal cells than adult cells, were probably more prone to create inhibitory synapses and that an increase in inhibitory versus excitatory synapses -that can be described also as an imbalance of GABA/Glutamate system- may also account for the symptoms observed in patients affected by congenital RTT.



If a direct correlation between FOXG1 and glutamate/GABA balance is confirmed, RTT, which today is not curable, might be eventually treated by reestablishing the normal equilibrium between excitatory and inhibitory brain synapses. The same scenario could be figured out in RTT caused by MECP2 and CDKL5.



Patriarchi T. et al. Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1(+/-) patients and in foxg1(+/-) mice. Eur J Hum Genet. 2015 Oct 7.

Livide G. et al. GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells. Eur J Hum Genet. 2015 Feb;23(2):195-201.