Genetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency.
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.
Cheli
Verónica T
VT
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Daniels
Richard W
RW
Godoy
Ruth
R
Hoyle
Diego J
DJ
Kandachar
Vasundhara
V
Starcevic
Marta
M
Martinez-Agosto
Julian A
JA
Poole
Stephen
S
DiAntonio
Aaron
A
Lloyd
Vett K
VK
Chang
Henry C
HC
Krantz
David E
DE
Dell'Angelica
Esteban C
EC
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
C550346:BLOS1 protein, Drosophila; D029721:Drosophila Proteins; D005136:Eye Proteins; D009419:Nerve Tissue Proteins