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Retinitis pigmentosa (RP) is a group of hereditary human diseases that cause retinal degeneration and lead to eventual blindness. More than 25% of all RP cases in humans appear to be caused by dominant mutations in the gene encoding the visual pigment rhodopsin. The mechanism by which the mutant rhodopsin proteins cause dominant retinal degeneration is still unclear. Interestingly, the great majority of these mutants appear to produce misfolded rhodopsin. We now report the isolation and characterization of 13 rhodopsin mutations that act dominantly to cause retinal degeneration in Drosophila; four of these correspond to identical substitutions in human autosomal dominant RP patients. We demonstrate that retinal degeneration results from interference in the maturation of wild-type rhodopsin by the mutant proteins.

The human pathogenic bacterium group A Streptococcus produces an extracellular cysteine protease [streptococcal pyrogenic exotoxin B (SpeB)] that is a critical virulence factor for invasive disease episodes. Sequence analysis of the speB gene from 200 group A Streptococcus isolates collected worldwide identified three main mature SpeB (mSpeB) variants. One of these variants (mSpeB2) contains an Arg-Gly-Asp (RGD) sequence, a tripeptide motif that is commonly recognized by integrin receptors. mSpeB2 is made by all isolates of the unusually virulent serotype M1 and several other geographically widespread clones that frequently cause invasive infections. Only the mSpeB2 variant bound to transfected cells expressing integrin ␣ v ␤ 3 (also known as the vitronectin receptor) or ␣ IIb ␤ 3 (platelet glycoprotein IIb-IIIa), and binding was blocked by a mAb that recognizes the streptococcal protease RGD motif region. In addition, mSpeB2 bound purified platelet integrin ␣ IIb ␤ 3 . Defined ␤ 3 mutants that are altered for fibrinogen binding were defective for SpeB binding. Synthetic peptides with the mSpeB2 RGD motif, but not the RSD sequence present in other mSpeB variants, blocked binding of mSpeB2 to transfected cells expressing ␣ v ␤ 3 and caused detachment of cultured human umbilical vein endothelial cells. The results (i) identify a Gram-positive virulence factor that directly binds integrins, (ii) identify naturally occurring variants of a documented Gram-positive virulence factor with biomedically relevant differences in their interactions with host cells, and (iii) add to the theme that subtle natural variation in microbial virulence factor structure alters the character of hostpathogen interactions.Group A Streptococcus (GAS) is a human pathogenic bacterium that causes diverse infections ranging in severity from relatively mild pharyngitis to life-threatening toxic shock syndrome and necrotizing fasciitis (1). GAS is composed of a heterogeneous array of chromosomal genotypes, and substantial levels of allelic variation also exist in genes encoding putative and proven virulence factors that mediate hostpathogen interactions (2-5). With the exception of M protein, whose structural variation helps GAS evade the type-specific immune response of the host (6), there has been little investigation of the potential ramifications of GAS allelic variation for host-pathogen interactions.GAS isolates produce a highly conserved extracellular cysteine protease known as streptococcal pyrogenic exotoxin B (SpeB) (reviewed in ref. 5). SpeB is initially expressed as a 40-kDa zymogen but then is converted to a 28-kDa active protease by proteolytic truncation (5, 7). SpeB is a critical virulence factor in two mouse models of invasive disease (8, 38) and human infections (5). Purified SpeB causes a cytopathic effect on cultured human endothelial cells (3) and has been shown to activate a host matrix metalloprotease (9).Integrins are heterodimeric membrane proteins located on the surface of mammalian cells that participate in ce...