Comparative Genomics and Gene Expression Analysis Identifies BBS9, a New Bardet-Biedl Syndrome Gene

Nishimura, Darryl; Swiderski, Ruth E.; Searby, Charles; Berg, Erik M.; Ferguson, Amanda L.; Hennekam, Raoul C. M.; Merin, Saul; Weleber, Richard G.; Biesecker, Leslie G.; Stone, Edwin M.; Sheffield, Val C.

doi:10.1086/498323

Cited by 194 publications

(138 citation statements)

References 36 publications

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“…Indeed, there are numerous reports of disease-causing deletions resulting from recombination between Alu elements (Batzer and Deininger, 2002;Nishimura et al, 2005;Casarin et al, 2006;Has et al, 2006;Kozak et al, 2006;Li et al, 2006;Matejas et al, 2006;Nissen et al, 2006;Sen et al, 2006;Shabbeer et al, 2006;Uddin et al, 2006;Xie et al, 2006;Zhang et al, 2006). If a large proportion of Alu elements indeed fosters euchromatic domains as suggested by the aforementioned study (Willoughby et al, 2000), then flanking sequences may also be destabilized.…”

Section: Non-random Repeat Distributions Via Natural Selectionmentioning

confidence: 94%

Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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Housekeeping genes are expressed across a wide variety of tissues. Since repetitive sequences have been reported to influence the expression of individual genes, we employed a novel approach to determine whether housekeeping genes can be distinguished from tissue-specific genes their repetitive sequence context. We show that Alu elements are more highly concentrated around housekeeping genes while various longer (>400-bp) repetitive sequences ("repeats"), including Long Interspersed Nuclear Element 1 (LINE-1) elements, are excluded from these regions. We further show that isochore membership does not distinguish housekeeping genes from tissue-specific genes and that repetitive sequence environment distinguishes housekeeping genes from tissue-specific genes in every isochore. The distinct repetitive sequence environment, in combination with other previously published sequence properties of housekeeping genes, were used to develop a method of predicting housekeeping genes on the basis of DNA sequence alone. Using expression across tissue types as a measure of success, we demonstrate that repetitive sequence environment is by far the most important sequence feature identified to date for distinguishing housekeeping genes.

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Section: Non-random Repeat Distributions Via Natural Selectionmentioning

confidence: 94%

Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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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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“…Whereas BBS4 and BBS8 are tetratricopeptide repeat (TPR) domain proteins , BBS1, BBS2, and BBS7 are putative ␤-propeller proteins (Badano et al, 2003). These distinctive domains of these proteins have been suggested to be involved in protein interactions, although BBS5 (Li et al, 2004) and BBS9 (Nishimura et al, 2005) have no obvious motifs. Thus, BBS genes are suggested to be involved in motor-driven intraflagellar and intracellular transport through their ability to mediate protein interactions.…”

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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Comparative Genomics and Gene Expression Analysis Identifies BBS9, a New Bardet-Biedl Syndrome Gene

Cited by 194 publications

References 36 publications

Repetitive sequence environment distinguishes housekeeping genes

Repetitive sequence environment distinguishes housekeeping genes

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

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

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