Human Molecular Genetics Advance Access originally published online on September 12, 2007
Human Molecular Genetics 2007 16(23):2933-2943; doi:10.1093/hmg/ddm254
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Reduced life span with heart and muscle dysfunction in Drosophila sarcoglycan mutants
1 Department of Medicine and 2 Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA and 3 Department of Medicine, 4 Department of Cell Biology and 5 Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27110, USA
* To whom correspondence should be addressed: Department of Medicine, Section of Cardiology, University of Chicago, 5841 S. Maryland, MC6088, Chicago, IL 60637, USA. Tel: +1 7737022679; Fax: +1 7737022681; Email: emcnally{at}uchicago.edu
Received July 24, 2007; Accepted August 24, 2007
In humans, genetically diverse forms of muscular dystrophy are associated with a disrupted sarcoglycan complex. The sarcoglycan complex resides at the muscle plasma membrane where it associates with dystrophin. There are six known sarcoglycan proteins in mammals whereas there are only three in Drosophila melanogaster. Using imprecise P element excision, we generated three different alleles at the Drosophila 
-sarcoglycan locus. Each of these deletions encompassed progressively larger regions of the -sarcoglycan gene. Line 840 contained a large deletion of the -sarcoglycan gene, and this line displayed progressive impairment in locomotive ability, reduced heart tube function and a shortened life span. In line 840, deletion of the Drosophila -sarcoglycan gene produced disrupted flight muscles with shortened sarcomeres and disorganized M lines. Unlike mammalian muscle where degeneration is coupled with ongoing regeneration, no evidence for regeneration was seen in this Drosophila sarcoglycan mutant. In contrast, line 28 was characterized with a much smaller deletion that affected only a portion of the cytoplasmic region of the -sarcoglycan protein and left intact the transmembrane and extracellular domains. Line 28 had a very mild phenotype with near normal life span, intact cardiac function and normal locomotive activity. Together, these data demonstrate the essential nature of the transmembrane and extracellular domains of Drosophila -sarcoglycan for normal muscle structure and function.