BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus

Stoetzel, Corinne; Laurier, Virginie; Davis, Erica E.; Muller, Jean; Rix, Suzanne; Badano, José L.; Leitch, Carmen C.; Salem, Nabiha; Chouery, Éliane; Corbani, Sandra; Jalk, Nadine; Vicaire, Serge; Sarda, Pierre; Hamel, C.; Lacombe, Didier; Holder, Muriel; Odent, Sylvie; Holder, Susan; Brooks, Alice S.; Elçioğlu, Nursel; Silva, Eduardo D.; Rossillion, Béatrice; Sigaudy, Sabine; Ravel, Thomy de; Lewis, Richard A.; Leheup, Bruno; Verloes, Alain; Amati‐Bonneau, Patrizia; Mégarbané, André; Poch, Olivier; Bonneau, Dominique; Beales, Philip L.; Mandel, Jean‐Louis; Katsanis, Nicholas; Dollfus, Hélène

doi:10.1038/ng1771

Cited by 259 publications

(264 citation statements)

References 15 publications

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“…In order to map novel BBS genes we undertook genetic linkage studies in a large Omani BBS kindred. We mapped a novel locus to chromosome 12q21.2 that overlapped the recently described BBS10 locus 21 and, furthermore, confirmed mutations in the BBS10 gene, FLJ23560. We also excluded linkage to the recently described BBS11 locus on chromosome 9q33.…”

Section: Introductionmentioning

confidence: 72%

Autozygosity mapping of Bardet–Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10

et al. 2006

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Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by variable obesity, pigmentary retinopathy, polydactyly, mental retardation, hypogonadism and renal failure. In order to identify novel BBS loci we undertook autozygosity mapping studies using high-density SNP microarrays in consanguineous kindreds. We mapped a BBS locus to a 10.1 Mb region at 12q15-q21.2 in a large Omani BBS family (peak lod score 8.3 at h ¼ 0.0 for marker D12S1722) that contained the recently described BBS10 locus. Mutation analysis of candidate genes within the target interval, including the BBS10 gene, revealed a homozygous frameshift mutation in FLJ23560 and mutations were also detected in four smaller consanguineous families with regions of autozygosity at 12q21.2. These findings (a) confirm a previous report that FLJ23560 (BBS10) mutations are a significant cause of BBS, and (b) further demonstrate the utility of high-density SNP array mapping in consanguineous families for the mapping and identification of recessive disease genes.

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Section: Introductionmentioning

confidence: 72%

Autozygosity mapping of Bardet–Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10

et al. 2006

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“…Thus, rhodopsin is a candidate protein that would be transported with assistance of BBS proteins, including MKKS, although other target proteins also must exist. In addition to MKKS , BBS10 (Stoetzel et al, 2006), and BBS12 (Stoetzel et al, 2007) are now known to share weak but significant sequence similarity to the group II chaperonins, including CCT. These proteins might assist protein transport by performing chaperone-like activities, although the exact molecular mechanisms of MKKS-dependent transport remain to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Amino acid sequence similarity between MKKS protein and group II chaperonins suggests that MKKS function may have evolved from the chaperonin family . In addition to MKKS, two other BBS proteins, BBS10 (Stoetzel et al, 2006) and BBS12 (Stoetzel et al, 2007), were recently shown to share weak but significant sequence similarities with group II chaperonins. Interestingly, none of the three chapeonin-like BBS proteins were found in the BBSome (Nachury et al, 2007), suggesting that these chaperonin like proteins have a distinctive role in BBS-associated functions.…”

Section: Introductionmentioning

confidence: 99%

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

Hirayama

Yamazaki²,

Kitamura³

et al. 2008

MBoC

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McKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease characterized by several developmental anomalies. Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder with pleiotropic symptoms. However, little is known about how MKKS mutations lead to disease. Here, we show that disease-causing mutants of MKKS are rapidly degraded via the ubiquitin-proteasome pathway in a manner dependent on HSC70 interacting protein (CHIP), a chaperone-dependent ubiquitin ligase. Although wild-type MKKS quickly shuttles between the centrosome and cytosol in living cells, the rapidly degraded mutants often fail to localize to the centrosome. Inhibition of proteasome functions causes MKKS mutants to form insoluble structures at the centrosome. CHIP and partner chaperones, including heat-shock protein (HSP)70/heat-shock cognate 70 and HSP90, strongly recognize MKKS mutants. Modest knockdown of CHIP by RNA interference moderately inhibited the degradation of MKKS mutants. These results indicate that the MKKS mutants have an abnormal conformation and that chaperone-dependent degradation mediated by CHIP is a key feature of MKKS/BBS diseases. INTRODUCTIONMcKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease predominantly characterized by developmental anomalies, including vaginal atresia with hydrometrocolpos, polydactyly, and congenital heart defects (McKusick et al., 1964). The MKKS gene encodes a 570-amino acid polypeptide with weak but significant similarity to group II chaperonins . Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder characterized by obesity, retinal dystrophy, polydactyly, mental retardation, renal malformation, and hypogenitalism (Beales et al., 1999), and thus MKKS is also called BBS6. 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). Retrograde transport of melanosomes in zebrafish is slowed by knockdown of BBS2 or BBS4-8 (Yen et al., 2006), whereas mutations in Caenorhabditis elegans BBS7 and BBS8 cause delays in intraflagellar transport driven by kinesin motors (Ou et al., 2005). The Chlamydomonas homologue of BBS5 is essential for flagellum formation (Li et al., ...

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“…This disorder is characterized by retinitis pigmentosa, renal malformations, situs inversus, cardiomyopathy, diabetes and polydactyly. Mutations in a number of genes are known to cause BBS, and there is evidence that all BBS proteins participate in a common cellular process, given that mutations in any BBS gene result in clinically related phenotypes (Katsanis, 2004;Nishimura et al, 2005;Stoetzel et al, 2006). BBS proteins are located at the basal body of cilia and centrosomes (during cell cycle), and it is proposed that these proteins assist microtubule-related transport and cellular organization processes relating to ciliary and centrosomal activities (Kim et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Ftm is a novel basal body protein of cilia involved in Shh signalling

et al. 2007

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In this study we show in mice that Ftm (Rpgrip1l) is located at the ciliary basal body. Our data reveal that Ftm is necessary for developmental processes such as the establishment of left-right asymmetry and patterning of the neural tube and the limbs. The loss of Ftm affects the ratio of Gli3 activator to Gli3 repressor, suggesting an involvement of Ftm in Shh signalling. As Ftm is not essential for cilia assembly but for full Shh response, Ftm can be considered as a novel component for cilium-related Hh signalling. Furthermore, the absence of Ftm in arthropods underlines the divergence between vertebrate and Drosophila Hh pathways.

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BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus

Cited by 259 publications

References 15 publications

Autozygosity mapping of Bardet–Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10

Autozygosity mapping of Bardet–Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10

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

Ftm is a novel basal body protein of cilia involved in Shh signalling

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