The PTCHD1 protein: A prominent actor in brain function and in neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) encompass a broad spectrum of conditions, including intellectual disability (ID), Attention Deficit Hyperactivity Disorders (ADHD) and autism spectrum disorders (ASD), often linked to disrupted synaptic functionality. Among the major NDD genes, PTCHD1 (Patched Domain Containing 1) encodes a transmembrane protein which acts as a crucial regulator of synaptic function. Mutations and microdeletions in PTCHD1 have been associated with global developmental delays such as ID, ASD, and behavioral abnormalities. This review explores the neurodevelopmental functions of PTCHD1, particularly its position within the synaptic environment, from the association with the postsynaptic proteome to the regulation of several major neuronal signaling pathways, cholesterol homeostasis and receptor trafficking. In a pathophysiological context, studies in Ptchd1 knockout mouse models revealed abnormal behavioral phenotypes, linked to synaptic impairments, including reduced excitatory postsynaptic currents and altered dendritic morphology similarly to recent results on human-derived neuronal models. By synthesizing findings from genetic, molecular, and behavioral studies, this review underscores the multifaceted roles of PTCHD1 in neurodevelopment and synaptic regulation. Understanding its function in synaptic pathways may provide crucial insights into the pathophysiology of NDDs, emphasizing the need for further research to clarify its role as a potential synaptic, orphan receptor.