Key Points A phenotype with albinism, early-onset seizures, neurodevelopmental delay, infection susceptibility, and neutropenia is caused by AP3D1 mutations. AP3δ deficiency destabilizes the AP3 complex and defines a novel type of Hermansky-Pudlak syndrome with severe neurologic involvement.

Highlights d Assembly of native AMPARs occurs in discrete steps defined by ER-resident interactors d ABHD6 nurses GluA monomers; FRRS1l/CPT1c complexes drive multimer-formation of GluAs d FRRS1l is a potent regulator of synapse maturation and synaptic plasticity d FRRS1l knockout phenocopies the severe intellectual disability of human patients

Tyrosine kinase 2 (TYK2) associates with interferon (IFN) alpha receptor, IL-10 receptor (IL-10R) beta and other cytokine receptor subunits for signal transduction, in response to various cytokines, including type-I and type-III IFNs, IL-6, IL-10, IL-12 and IL-23. Data on TYK2 dependence on cytokine responses and in vivo consequences of TYK2 deficiency are inconsistent. We investigated a TYK2 deficient patient, presenting with eczema, skin abscesses, respiratory infections and IgE levels >1000 U/mL, without viral or mycobacterial infections and a corresponding cellular model to analyze the role of TYK2 in type-III IFN mediated responses and NK-cell function. We established a novel simple diagnostic monocyte assay to show that the mutation completely abolishes the IFN-α mediated antiviral response. It also partly reduces IL-10 but not IL-6 mediated signaling associated with reduced IL-10Rβ expression. However, we found almost normal type-III IFN signaling associated with minimal impairment of virus control in a TYK2 deficient human cell line. Contrary to observations in TYK2 deficient mice, NK-cell phenotype and function, including IL-12/IL-18 mediated responses, were normal in the patient. Thus, preserved type-III IFN responses and normal NK-cell function may contribute to antiviral protection in TYK2 deficiency leading to a surprisingly mild human phenotype.

Spatial relationships between Ca channels and release sensors at active zones (AZs) are a major determinant of synaptic fidelity. They are regulated developmentally, but the underlying molecular mechanisms are largely unclear. Here, we show that Munc13-3 regulates the density of Ca2.1 and Ca2.2 channels, alters the localization of Ca2.1, and is required for the development of tight, nanodomain coupling at parallel-fiber AZs. We combined EGTA application and Ca-channel pharmacology in electrophysiological and two-photon Ca imaging experiments with quantitative freeze-fracture immunoelectron microscopy and mathematical modeling. We found that a normally occurring developmental shift from release being dominated by Ca influx through Ca2.1 and Ca2.2 channels with domain overlap and loose coupling (microdomains) to a nanodomain Ca2.1 to sensor coupling is impaired in Munc13-3-deficient synapses. Thus, at AZs lacking Munc13-3, release remained triggered by Ca2.1 and Ca2.2 microdomains, suggesting a critical role of Munc13-3 in the formation of release sites with calcium channel nanodomains.