DTNBP1

This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. A similar protein in mouse is a component of a protein complex termed biogenesis of lysosome-related organelles complex 1 (BLOC-1), and binds to alpha- and beta-dystrobrevins, which are components of the dystrophin-associated protein complex (DPC). Mutations in this gene are associated with Hermansky-Pudlak syndrome type 7. This gene may also be associated with schizophrenia. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq]

dystrobrevin binding protein 1

Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Associates with the BLOC-2 complex to facilitate the transport of TYRP1 independent of AP-3 function. Plays a role in synaptic vesicle trafficking and in neurotransmitter release. Plays a role in the regulation of cell surface exposure of DRD2. May play a role in actin cytoskeleton reorganization and neurite outgrowth. May modulate MAPK8 phosphorylation. Appears to promote neuronal transmission and viability through regulating the expression of SNAP25 and SYN1, modulating PI3-kinase-Akt signaling and influencing glutamatergic release. Regulates the expression of SYN1 through binding to its promoter. Modulates prefrontal cortical activity via the dopamine/D2 pathway.

Actin cytoskeleton reorganization Source: UniProtKB
Anterograde axonal transport Source: UniProtKB
Anterograde synaptic vesicle transport Source: UniProtKB
Blood coagulation Source: Ensembl
Dendrite morphogenesis Source: Ensembl
Melanosome organization Source: UniProtKB
Negative regulation of protein binding Source: Ensembl
Negative regulation of protein kinase activity Source: GO_Central
Negative regulation of protein serine/threonine kinase activity Source: Ensembl
Neuron projection development Source: UniProtKB
Neuron projection morphogenesis Source: UniProtKB
Platelet dense granule organization Source: GO_Central
Positive regulation of gene expression Source: UniProtKB
Positive regulation of neurotransmitter secretion Source: UniProtKB
Regulation of dopamine receptor signaling pathway Source: UniProtKB
Regulation of dopamine secretion Source: UniProtKB
Regulation of JUN kinase activity Source: Ensembl
Regulation of synaptic vesicle exocytosis Source: GO_Central

Isoform 1: Endosome membrane; Cytoplasm; Nucleus; Endoplasmic reticulum; Cytoplasmic vesicle membrane; Melanosome membrane; Postsynaptic density. Mainly cytoplasmic but shuttles between the cytoplasm and nucleus. Exported out of the nucleus via its NES in a XPO1-dependent manner. Nuclear localization is required for regulation of the expression of genes such as SYN1. Detected in neuron cell bodies, axons and dendrites. Mainly located to the postsynaptic density. Detected at tubulovesicular elements in the vicinity of the Golgi apparatus and of melanosomes. Occasionally detected at the membrane of pigmented melanosomes in cultured melanoma cells. The BLOC-1 complex associates with the BLOC-2 complex in early endosome-associated tubules.
Isoform 2: Endosome membrane; Postsynaptic cell membrane; Cytoplasm; Nucleus; Endoplasmic reticulum; Cytoplasmic vesicle membrane; Synaptic vesicle membrane; Melanosome membrane. Shuttles between the cytoplasm and nucleus. Exported out of the nucleus via its NES in a XPO1-dependent manner. Nuclear localization is required for regulation of the expression of genes such as SYN1. Mainly expressed in the dendritic spine. Predominantly a synaptic vesicle isoform but also highly expressed in the nucleus. The BLOC-1 complex associates with the BLOC-2 complex in early endosome-associated tubules. Associated with the AP-3 complex at presynaptic terminals.
Isoform 3: Endosome membrane; Postsynaptic cell membrane; Cytoplasm; Endoplasmic reticulum; Cytoplasmic vesicle membrane; Synaptic vesicle membrane; Melanosome membrane. Exclusivley cytoplasmic. Predominantly found in the postsynaptic density (PSD). Little association with synaptic vesicles. The BLOC-1 complex associates with the BLOC-2 complex in early endosome-associated tubules. Associated with the AP-3 complex at presynaptic terminals.

Hermansky-Pudlak syndrome 7 (HPS7):
A form of Hermansky-Pudlak syndrome, a genetically heterogeneous autosomal recessive disorder characterized by oculocutaneous albinism, bleeding due to platelet storage pool deficiency, and lysosomal storage defects. This syndrome results from defects of diverse cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. Ceroid storage in the lungs is associated with pulmonary fibrosis, a common cause of premature death in individuals with HPS.
Defects in DTNBP1 are associated with susceptibility to schizophrenia, a mental disorder characterized by a breakdown of thought processes and by poor emotional responsiveness. Genetic mutations lead to alterations in the glutamatergic transmission in the brain and modified Akt signaling (PubMed:15345706). Protein levels and expression are reduced in nerve terminals of the hippocampus and there is an increased release of glutamate in schizophrenic patients (PubMed:15124027). Levels of isoform 1 are reduced in the pSTG, but not in HF, by about 48% in 92% of schizophrenic patients. In the HF, there is an average of 33% reduction in synaptic expression of isoform 2 in 67% of cases, and of isoform 3, an average reduction of 35% in 80% of cases. In the dorsolateral prefrontal cortex (DLPFC), significant reductions in levels of isoform 3 are observed about 71% of schizophrenic patients showed an average reduction of this isoform of about 60% (PubMed:19617633).

Ubiquitinated by TRIM32. Ubiquitination leads to DTNBP1 degradation.
Isoforms 1 and 2 highly phosphorylated by PRKDC in vitro. Isoform 3 only weakly phosphorylated by PRKDC in vitro.