<i>Bbs2</i>
            -null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin

Nishimura, Darryl; Fath, Melissa A.; Mullins, Robert F.; Searby, Charles; Andrews, Michael; Davis, Rowland H.; Andorf, Jeaneen L.; Mykytyn, Kirk; Swiderski, Ruth E.; Yang, Baoli; Carmi, Rivka; Stone, Edwin M.; Sheffield, Val C.

doi:10.1073/pnas.0405496101

Cited by 349 publications

(421 citation statements)

References 28 publications

Supporting

Mentioning

380

Contrasting

Unclassified

Order By: Relevance

“…Second, there are three relevant knockout mouse models for genes within the linked interval: Pappa (31), Astn1 (paralogue of Astn2) (32), and Tlr4 (33). These models do not have phenotypes that resemble BBS mouse models (34)(35)(36). Finally, functional characterization of other TRIM proteins indicates involvement with components of the cytoskeleton, a finding consistent with the function of other BBS proteins (37)(38)(39).…”

Section: Discussionsupporting

confidence: 56%

Homozygosity mapping with SNP arrays identifiesTRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11)

Chiang

Beck

Yen

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

389

295

View full text Add to dashboard Cite

The identification of mutations in genes that cause human diseases has largely been accomplished through the use of positional cloning, which relies on linkage mapping. In studies of rare diseases, the resolution of linkage mapping is limited by the number of available meioses and informative marker density. One recent advance is the development of high-density SNP microarrays for genotyping. The SNP arrays overcome low marker informativity by using a large number of markers to achieve greater coverage at finer resolution. We used SNP microarray genotyping for homozygosity mapping in a small consanguineous Israeli Bedouin family with autosomal recessive Bardet-Biedl syndrome (BBS; obesity, pigmentary retinopathy, polydactyly, hypogonadism, renal and cardiac abnormalities, and cognitive impairment) in which previous linkage studies using short tandem repeat polymorphisms failed to identify a disease locus. SNP genotyping revealed a homozygous candidate region. Mutation analysis in the region of homozygosity identified a conserved homozygous missense mutation in the TRIM32 gene, a gene coding for an E3 ubiquitin ligase. Functional analysis of this gene in zebrafish and expression correlation analyses among other BBS genes in an expression quantitative trait loci data set demonstrate that TRIM32 is a BBS gene. This study shows the value of high-density SNP genotyping for homozygosity mapping and the use of expression correlation data for evaluation of candidate genes and identifies the proteasome degradation pathway as a pathway involved in BBS.genetic mapping ͉ obesity ͉ SNP genotyping ͉ zebrafish model

show abstract

Section: Discussionsupporting

confidence: 56%

Homozygosity mapping with SNP arrays identifiesTRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11)

Chiang

Beck

Yen

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

389

295

View full text Add to dashboard Cite

show abstract

“…The phenotypes of the MKKS-knockout mouse (Fath et al, 2005) closely resemble those of mice disrupted for the BBS1, BBS2, or BBS4 genes (Kulaga et al, 2004;Nishimura et al, 2004), and many of these phenotypes have been suggested to be caused by ciliary dysfunction. In the case of the BBS2-knockout mouse, the photoreceptor degeneration is preceded by mislocalization of rhodopsin, which indicates a defect in protein transport.…”

Section: Discussionmentioning

confidence: 94%

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

Hirayama

Yamazaki²,

Kitamura³

et al. 2008

MBoC

View full text Add to dashboard Cite

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., ...

show abstract

“…53 Rod-cone dystrophy is thought to be a consequence of abnormal trafficking across the defective modified cilia connecting the inner and outer segments of photoreceptors leading to apoptosis. 50,54,55 Receptors for sonic hedgehog signalling are found on cilia in the developing limb buds. 55 IFT proteins are thought to modulate this pathway 39 and dysregulation has been associated with the limb malformations observed in ciliopathies.…”

Section: Biology Of the Diseasementioning

confidence: 99%

Bardet–Biedl syndrome

2012

View full text Add to dashboard Cite

Bbs2 -null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin

Cited by 349 publications

References 28 publications

Homozygosity mapping with SNP arrays identifiesTRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11)

Homozygosity mapping with SNP arrays identifiesTRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11)

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

Bardet–Biedl syndrome

Contact Info

Product

Resources

About