Disease relevance of Ap3d1

• The mouse mutant mocha, a model for the Hermansky-Pudlak storage pool deficiency syndrome, is characterized by defective platelets, coat and eye color dilution, lysosomal abnormalities, inner ear degeneration, and neurological deficits [1].
• A mouse cDNA (mBLVR1) which was highly homologous to the bovine cDNA of the bovine leukemia virus receptor (BLVR) gene was cloned [2].
• Mice mutant for a second allele, mh(2J), are as hyperactive as mh, and display both spike wave absence and generalized tonic clonic seizures, but have less coat color dilution, no hearing loss, and no hypersynchronized EEG [3].
• Using mocha mice, which are deficient in functional AP-3, we identify an AP-3-dependent tetanus neurotoxin-resistant asynchronous release that can be evoked at hippocampal mossy fiber (MF) synapses [4].
• All mutants, except mocha and achondroplasia, displayed normal mating behavior [5].

High impact information on Ap3d1

• Whereas the mocha and pearl SPD mutants have defects in Ap-3, our findings suggest that pa SPD mutants are defective in a more downstream event of vesicle-trafficking: namely, vesicle-docking and fusion [6].
• In mocha brain, the ZnT-3 transporter is reduced, resulting in a lack of zinc-associated Timm historeactivity in hippocampal mossy fibers [1].
• Here, we show that mocha is a null allele of the delta subunit of the adaptor-like protein complex AP-3, which is associated with coated vesicles budding from the trans-Golgi network, and that AP-3 is missing in mocha tissues [1].
• Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles [1].
• In addition, quantal release in mocha cultures is more frequent and more sensitive to sucrose [4].

Biological context of Ap3d1

• We examined retinal function and histology of the mocha mutant [7].
• We found that not only mocha homozygotes but also other littermates in the inbred strain are blind due to severe defects in both rod and cone photoreceptors on electroretinogram recordings [7].
• The mBLVR1 cDNA, of 4,730 bp, covered nearly the full length of the mRNA (about 5 kb) and included an open reading frame (ORF) encoding a protein of 1,199 amino acids [2].
• Depth electrode recordings of hippocampal auditory evoked potentials revealed that the response to the first of two paired tones was significantly enhanced in mocha and mocha2J, as compared with littermate controls [8].
• Mouse models deficient in AP-3, mocha, develop a neurological phenotype of which the central feature is an alteration of the luminal synaptic vesicle composition [9].

Anatomical context of Ap3d1

• Mocha (mh) is one of several recessive mouse mutants characterized by platelet storage pool disorder, pigment abnormalities, reduced fertility, kidney function deficiencies, and, in some mutants, inner ear and natural killer cell deficiencies [10].
• Photoreceptor degeneration and rd1 mutation in the grizzled/mocha mouse strain [7].
• The pearl (HPS2) and mocha genes encode the beta3A and delta subunits, respectively, of the AP-3 adaptor complex, which captures organelle membrane proteins at the trans-Golgi apparatus [11].
• The trans-Golgi/endosome adaptor-related complex AP-3 is missing in mh mice owing to a deletion in the gene encoding the delta subunit [3].
• Intracellular transport of MHC class II and associated invariant chain in antigen presenting cells from AP-3-deficient mocha mice [12].

Associations of Ap3d1 with chemical compounds

• The pronounced theta rhythm characteristic of unanesthetized mocha mice was not observed in these chloral-hydrate anesthetized mice, whereas spike discharge activity was frequently present in the recordings [8].
• The otolith defects of mocha mice were prevented or reduced by supplementing the pregnant dams with manganese and/or zinc [13].
• Abundance of zinc ions in synaptic terminals of mocha mutant mice: zinc transporter 3 immunohistochemistry and zinc sulphide autometallography [14].

Other interactions of Ap3d1

• Thus, genetic mapping of the gr locus will also yield information about the mh location [10].
• Genotyping confirmed the presence of a viral insertion of rd1 gene in the mocha strain [7].
• While mh mice show a severe reduction of vesicular zinc (TIMM staining) owing to mislocalization and degradation of the Zinc transporter ZnT-3, the TIMM and ZnT-3 staining patterns in mh(2J) varies, with normal expression in hippocampal mossy fibers, but abnormal patterns in neocortex [3].
• In this study, we identified a chloride channel, ClC-3, whose level in synaptic vesicles and hippocampal mossy fiber terminals was reduced in the context of the mocha AP-3 deficiency [9].

References