Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport

Abstract

From a handful of uncloned genetic loci 6 years ago, great strides have been made in understanding the genetic and molecular aetiology of Bardet-Biedl syndrome (BBS), a rare pleiotropic disorder characterised by a multitude of symptoms, including obesity, retinal degeneration and cystic kidneys. Presently, 11 BBS genes have been cloned, with the likelihood that yet more BBS genes remain undiscovered. In 2003, a major breakthrough was made when it was shown that BBS is likely caused by defects in basal bodies and/or primary cilia. Since then, studies in numerous animal models of BBS have corroborated the initial findings and, in addition, have further refined the specific functions of BBS proteins. These include roles in establishing planar cell polarity (noncanonical Wnt signaling) in mice and zebrafish, modulating intraflagellar transport and lipid homeostasis in worms, and regulating intracellular trafficking and centrosomal functions in zebrafish and human tissue culture cells. From these discoveries, a common theme has emerged, namely that the primary function of BBS proteins may be to mediate and regulate microtubule-based intracellular transport processes.

Bardet–Biedl syndrome

“…39 BBS proteins have been demonstrated to regulate IFT and lipid homoeostasis in worms and modulate intracellular trafficking and centrosomal function in zebrafish. 59 Mouse models share many of the phenotypic features observed in humans affected with BBS and therefore serve as an excellent mammalian model of the disease. Simons et al 60 demonstrated this with successful gene therapy preventing photoreceptor death in the BBS4-null murine model.…”

MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination

“…Twelve of the genes that are responsible for BBS (BBS1-12) have been identified so far, and the products of several of these genes have been suggested to be involved in intraflagellar transport in cilia and intracellular trafficking in the cytosol Badano et al, 2005;Beales, 2005;Blacque and Leroux, 2006). Cargo-carrying motors play crucial roles in intraflagellar and intracellular transport systems by bidirectionally moving on microtubules, and BBS4 interacts with the dynactin complex, which mediates interactions between cargoes and the dynein motor (Kim et al, 2004).…”

“…The MKKS mRNA is widely expressed in various tissues, including those affected by MKKS and BBS diseases . Although more than 10 mutations in the MKKS gene have been identified in patients (Beales et al, 2001;Slavotinek et al, 2002), little is known about how they cause MKKS and BBS.Twelve of the genes that are responsible for BBS (BBS1-12) have been identified so far, and the products of several of these genes have been suggested to be involved in intraflagellar transport in cilia and intracellular trafficking in the cytosol Badano et al, 2005;Beales, 2005;Blacque and Leroux, 2006). Cargo-carrying motors play crucial roles in intraflagellar and intracellular transport systems by bidirectionally moving on microtubules, and BBS4 interacts with the dynactin complex, which mediates interactions between cargoes and the dynein motor (Kim et al, 2004).…”

Association between BBS6/MKKS gene polymorphisms, obesity and metabolic syndrome in the Greek population

“…It is a genetically heterogeneous syndrome and pathogenic mutations have been identified in many genes. 3 It is now evident that all of the known BBS proteins are components of the centrosome and/or basal body and have an impact on ciliary transport. 3,4 Other centrosomal disorders also share phenotypic aspects of BBS, particularly obesity, suggesting a link between these proteins and organelles and the pathogenesis of obesity.…”

“…3 It is now evident that all of the known BBS proteins are components of the centrosome and/or basal body and have an impact on ciliary transport. 3,4 Other centrosomal disorders also share phenotypic aspects of BBS, particularly obesity, suggesting a link between these proteins and organelles and the pathogenesis of obesity. Recently, Forti et al 5 reported for the first time that BBS proteins are expressed with a unique pattern during adipogenesis.…”