Details

Autor(en) / Beteiligte

• Cheli, Verónica 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.

Titel

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

Ist Teil von

• Human molecular genetics, 2010-03, Vol.19 (5), p.861-878

Ort / Verlag

Oxford: Oxford University Press

Erscheinungsjahr

2010

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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.