About DLG4 Synaptopathy and SHINE Syndrome Foundation

What are DLG4, PSD-95, and SHINE Syndrome?

If you have a loved one who is newly diagnosed with DLG4 Synaptopathy, you may quickly be overwhelmed by medical terms, definitions, and a myriad of unanswered questions.  This and the research page on this site are meant to provide families with a consolidated resource for DLG4-related information.  Please remember to reach out through the social media links or form below to help us grow our amazing community!

SHINE syndrome, 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 SHINE syndrome also present with sleep disturbances, skeletal (bone) abnormalities, and/or structural brain abnormalities (seen on an MRI).

SHINE syndrome 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 SHINE syndrome.

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 SHINE-syndrome, and to develop targeted therapeutic interventions.

SHINE syndrome is inherited in an autosomal dominant fashion. This means that only a single copy of the disease-associated mutation is enough to cause the disease. Most individuals with SHINE syndrome are found to have de novo (new) variants in DLG4, meaning the variant occurs for the first time in them and is not inherited from a parent. There are families, however, where there has been sibling reoccurrence of SHINE syndrome. This is hypothesized to be due to a phenomenon known as mosaicism (the variant is present in small amount of the parent’s cells, but all of the child’s cells).

Where to Next?

Check out our Community, Resources, or Media pages for some additional details. Or if you want to get into the more technical aspects, wander over to the Research section for in-depth details on SHINE Syndrome and the steps being taken to treat it.