title: Genetic and phenotypic analysis of the mouse mutant mh2J, an Ap3d allele caused by IAP element insertion.
abstract: Mocha (mh), a mouse model for Hermansky-Pudlak syndrome (HPS), is characterized by platelet storage pool deficiency, pigment dilution, and deafness as well as neurological abnormalities. 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. 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. Here we show that the mh(2J) mutation is due to an IAP element insertion in the Ap3d gene leading to a C-terminally truncated protein. Despite correct assembly of the AP-3 complex and localization to the trans-Golgi network and endosomes, AP-3 function in neurons remains impaired. 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. These results indicate that the N-terminal portion of the delta subunit is sufficient for AP-3 complex assembly and subcellular localization to the TGN/endosomes, while subsequent function is regulated in part by cell-specific interactions with the C-terminal portion.
authors.affiliation: Mental Health Research Inst., University of Michigan, 205 Zina Pitcher Place, Ann Arbor 48109-0720, USA.
authors.forename: Prameela
authors.initials: P
authors.lastname: Kantheti
authors.forename: Maria E
authors.initials: ME
authors.lastname: Diaz
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Peden
authors.forename: Eunju E
authors.initials: EE
authors.lastname: Seong
authors.forename: David F
authors.initials: DF
authors.lastname: Dolan
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Robinson
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.forename: Margit L
authors.initials: ML
authors.lastname: Burmeister
mesh_terms: D000818:Animals; D004251:DNA Transposable Elements; D004195:Disease Models, Animal; D007426:Genes, Intracisternal A-Particle; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D004251:DNA Transposable Elements