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

被引：52

作者：

Cheli, Veronica T. ^{[1
]}

Daniels, Richard W. ^{[4
]}

Godoy, Ruth ^{[5
]}

Hoyle, Diego J. ^{[1
]}

Kandachar, Vasundhara ^{[6
]}

Starcevic, Marta ^{[1
]}

Martinez-Agosto, Julian A. ^{[1
,2
]}

Poole, Stephen ^{[7
]}

DiAntonio, Aaron ^{[4
]}

Lloyd, Vett K. ^{[5
]}

Chang, Henry C. ^{[6
]}

Krantz, David E. ^{[3
]}

Dell'Angelica, Esteban C. ^{[1
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA

[4] Washington Univ, Dept Dev Biol, St Louis, MO 63110 USA

[5] Mt Allison Univ, Dept Biol, Sackville, NB E4L 1G7, Canada

[6] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA

[7] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 05期

基金：

美国国家卫生研究院; 加拿大自然科学与工程研究理事会;

关键词：

HERMANSKY-PUDLAK-SYNDROME; SUSCEPTIBILITY GENE; PIGMENTATION GENE; AP-3; COMPLEX; MOUSE MODEL; WHITE GENE; PROTEIN; SCHIZOPHRENIA; DYSBINDIN; ENCODES;

D O I：

10.1093/hmg/ddp555

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：861 / 878

页数：18

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