title: Genetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency.
abstract: Biogenesis of lysosome-related organelles complex 1 (BLOC-1) is a protein complex formed by the products of eight distinct genes. Loss-of-function mutations in two of these genes, DTNBP1 and BLOC1S3, cause Hermansky-Pudlak syndrome, a human disorder characterized by defective biogenesis of lysosome-related organelles. In addition, haplotype variants within the same two genes have been postulated to increase the risk of developing schizophrenia. However, the molecular function of BLOC-1 remains unknown. Here, we have generated a fly model of BLOC-1 deficiency. Mutant flies lacking the conserved Blos1 subunit displayed eye pigmentation defects due to abnormal pigment granules, which are lysosome-related organelles, as well as abnormal glutamatergic transmission and behavior. Epistatic analyses revealed that BLOC-1 function in pigment granule biogenesis requires the activities of BLOC-2 and a putative Rab guanine-nucleotide-exchange factor named Claret. The eye pigmentation phenotype was modified by misexpression of proteins involved in intracellular protein trafficking; in particular, the phenotype was partially ameliorated by Rab11 and strongly enhanced by the clathrin-disassembly factor, Auxilin. These observations validate Drosophila melanogaster as a powerful model for the study of BLOC-1 function and its interactions with modifier genes.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Verónica T
authors.initials: VT
authors.lastname: Cheli
authors.forename: Richard W
authors.initials: RW
authors.lastname: Daniels
authors.forename: Ruth
authors.initials: R
authors.lastname: Godoy
authors.forename: Diego J
authors.initials: DJ
authors.lastname: Hoyle
authors.forename: Vasundhara
authors.initials: V
authors.lastname: Kandachar
authors.forename: Marta
authors.initials: M
authors.lastname: Starcevic
authors.forename: Julian A
authors.initials: JA
authors.lastname: Martinez-Agosto
authors.forename: Stephen
authors.initials: S
authors.lastname: Poole
authors.forename: Aaron
authors.initials: A
authors.lastname: DiAntonio
authors.forename: Vett K
authors.initials: VK
authors.lastname: Lloyd
authors.forename: Henry C
authors.initials: HC
authors.lastname: Chang
authors.forename: David E
authors.initials: DE
authors.lastname: Krantz
authors.forename: Esteban C
authors.initials: EC
authors.lastname: Dell'Angelica
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics*; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics / Q000378:metabolism; D006801:Humans; D023421:Models, Animal; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015388:Organelles / Q000378:metabolism; D010641:Phenotype
chemical_list: C550346:BLOS1 protein, Drosophila; D029721:Drosophila Proteins; D005136:Eye Proteins; D009419:Nerve Tissue Proteins