Abstract
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by obesity, retinal degeneration, polydactyly, hypogenitalism and renal defects. Recent findings have associated the etiology of the disease with cilia, and BBS proteins have been implicated in trafficking various ciliary cargo proteins. To date, 17 different genes have been reported for BBS among which BBS1 is the most common cause of the disease followed by BBS10, and BBS4. A murine model of Bbs4 is known to phenocopy most of the human BBS phenotypes, and it is being used as a BBS disease model. To better understand the in vivo localization, cellular function, and interaction of BBS4 with other proteins, we generated a transgenic BBS4 mouse expressing the human BBS4 gene under control of the beta actin promoter. The transgene is expressed in various tissues including brain, eye, testis, heart, kidney, and adipose tissue. These mice were further bred to express the transgene in Bbs4 null mice, and their phenotype was characterized. Here we report that despite tissue specific variable expression of the transgene, human BBS4 was able to complement the deficiency of Bbs4 and rescue all the BBS phenotypes in the Bbs4 null mice. These results provide an encouraging prospective for gene therapy for BBS related phenotypes and potentially for other ciliopathies.
Highlights
Bardet-Biedl syndrome (BBS) is a pleiotropic, autosomal recessive disorder with the primary clinical features of obesity, retinopathy, polydactyly, learning disabilities, hypogenitalism, and renal defects [1,2,3]
We report that despite tissue specific variable expression of the transgene, human BBS4 was able to complement the deficiency of Bbs4 and rescue all BBS phenotypes when crossed onto the Bbs4 null genetic background
Generation of Transgenic BBS4 We generated transgenic mice carrying human BBS4 tagged with a lap tag under the control of b-actin promoter
Summary
Bardet-Biedl syndrome (BBS) is a pleiotropic, autosomal recessive disorder with the primary clinical features of obesity, retinopathy, polydactyly, learning disabilities, hypogenitalism, and renal defects [1,2,3]. Components of the BBS phenotype are common, and debilitating including retinopathy, renal failure and obesity. BBS is a genetically heterogeneous disease, and 17 different causative genes have been reported to date. Among these 17 genes, BBS1 and BBS10 have been reported to be the most common cause of the disease [5]. Bbs42/2 mice are hypertensive, leptin resistant and have renal defects [9]. Due to these significant phenotypes, Bbs42/2 mice are commonly used as a BBS disease model
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