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

Verónica T. Cheli, Richard W. Daniels, Ruth Godoy, Diego J. Hoyle, Vasundhara Kandachar, Marta Starcevic, Julian A. Martinez-Agosto, Stephen Poole, Aaron di Antonio, Vett K. Lloyd, Henry C. Chang, David E. Krantz, Esteban C. Dell'Angelica

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44 Scopus citations


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.

Original languageEnglish
Article numberddp555
Pages (from-to)861-878
Number of pages18
JournalHuman molecular genetics
Issue number5
StatePublished - Mar 1 2010

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    Cheli, V. T., Daniels, R. W., Godoy, R., Hoyle, D. J., Kandachar, V., Starcevic, M., Martinez-Agosto, J. A., Poole, S., di Antonio, A., Lloyd, V. K., Chang, H. C., Krantz, D. E., & Dell'Angelica, E. C. (2010). Genetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency. Human molecular genetics, 19(5), 861-878. [ddp555].