Genetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency

作者：Cheli Veronica T; Daniels Richard W; Godoy Ruth; Hoyle Diego J; Kandachar Vasundhara; Starcevic Marta; Martinez Agosto Julian A; Poole Stephen; DiAntonio Aaron; Lloyd Vett K; Chang Henry C; Krantz David E; Dell'Angelica Esteban C^*

来源：Human Molecular Genetics, 2010, 19(5): 861-878.

DOI：10.1093/hmg/ddp555

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.

• 出版日期2010-3-1