Learn more about this rare disease, how it affects our families, and how we're helping to find treatment.
What is DLG4 Synaptopathy?
DLG4 SHINE, also known as DLG4-related synaptopathy, is an extremely rare neurodevelopmental disorder characterized predominantly by global developmental delay/intellectual disability of varying severity, autism spectrum disorder, attention deficit hyperactivity disorder, hypotonia, and epilepsy. Many individuals with DLG4 SHINE also present with sleep disturbances, skeletal (bone) abnormalities, and/or structural brain abnormalities (seen on an MRI).
A Synaptopathy is a disease of the brain that relates to the dysfunction of synapses. DLG4 stands for Discs Large MAGUK Scaffold Protein 4, and is mapped to the 17th chromosome.
The Role of DLG4 and PSD-95 in Brain Development & Function
DLG4 SHINE is caused by variants (genetic changes) in the gene DLG4, located on chromosome 17. DLG4 is an important gene that encodes the protein PSD-95 (Postsynaptic Density Protein 95), which plays a major role in brain development and function through its implications in synaptic strength and plasticity. These mechanisms, along with PSD-95’s role in organizing and interacting with other proteins, represent a gene with many capabilities of which, when altered, can induce susceptibility to DLG4-related Synatopathy.
PSD-95 is a synaptic scaffolding protein which plays a crucial role in organizing and stabilizing the components of postsynaptic density (PSD) in the excitatory synapses of the brain. PSD-95 binds to voltage-gated potassium channels (i.e. Kv1) and glutamate-gated ion channels (i.e. AMPA and NMDA receptors) and thereby regulates their localization and function. As such, abnormalities in PSD-95 expression and the resulting dysfunction in the scaffolding, anchoring, and interacting role of PSD-95 leads to disruptions of these ion channels directly causing channelopathy-induced disorder and symptoms.
DLG4-related synaptopathy is a neurodevelopmental disorder (NDD) caused by mutations in the DLG4 gene encoding PSD-95. The main symptoms are Sleeping disturbances, Hypotonia, Intellectual disability, Neurological disorders, and Epilepsy (hence coined as SHINE syndrome), and these symptoms overlap strikingly with the clinical features observed in NDDs associated with genes encoding subunits of Kv1-channels (KCNA1-2, KCNA4), and glutamate channels AMPAR (GRIA1-4) and NMDAR (GRIN1, GRIN2A-D, GRIN3A-B). The SHINE syndrome symptoms are therefore likely to be caused by PSD-95-dependent malfunction of its interaction with ion-channels. Understanding the intricate interplay between PSD-95 and ion channels and receptors is therefore essential for elucidating the function/dysfunction of synapses and unraveling the complex mechanisms underlying neurological and neurodevelopmental disorders, such as DLG4 SHINE, and to develop targeted therapeutic interventions.
Alterations in the expression of the PSD-95 protein have also been linked to schizophrenia, and Alzheimer’s disease. Presently there are less than two hundred patients with this diagnosis but it is possible that hundreds if not thousands exist around the world but remain undiagnosed due to economic barriers.
PSD-95 regulates synaptic function in the brain
Abnormalities in PSD-95 expression and the resulting dysfunction in the scaffolding, anchoring, and interacting role of PSD-95 leads to disruptions of these ion channels directly causing channelopathy-induced disorder and symptoms.