Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia

Shah, Alok S.; Farmen, Sara L.; Moninger, Thomas O.; Businga, Thomas R.; Andrews, Michael; Bugge, Kevin; Searby, Charles; Nishimura, Darryl; Brogden, Kim A.; Kline, Joel N.; Sheffield, Val C.; Welsh, Michael J.

doi:10.1073/pnas.0712327105

Cited by 107 publications

(94 citation statements)

References 45 publications

(46 reference statements)

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“…However, MCHR1 was often associated with bulges along the cilium in Bbs3 −/− cells. These bulges are similar to those found in the tracheal and ependymal cilia of BBS mutant mice (18,23), and reminiscent of bulges found in IFT complex A mutants (36,37). Similarly, endogenous Smo accumulates inside cilia without ligand stimulation.…”

Section: Discussionsupporting

confidence: 75%

“…The movement of motile cilia without bulges appears to be normal. Unlike the severe defects observed in motile cilia of the ventricle ependymal layer and spermatozoa flagella, trachea motile cilia appear grossly normal, although a small fraction of them have abnormal cilia morphology, as is seen in other BBS mutants (23). The ciliogenesis of trachea motile cilia may differ from other motile cilia, as a similar situation is observed in Tg737orpk mice.…”

Section: Discussionmentioning

confidence: 70%

“…The alteration of motility of ependymal cell cilia is most likely because of the accumulation of materials inside the bulges, although we cannot rule out the possibility of subtle defective axonemal structures. The accumulation of materials that appear vesicle-like has been shown in trachea motile cilia and motile cilia of ependymal cells of other BBS mutants (18,23). The movement of motile cilia without bulges appears to be normal.…”

Section: Discussionmentioning

confidence: 89%

“…mutant mice are able to form other motile cilia, such as tracheal cilia (23) and primary cilia, including the connecting cilia of photoreceptors. The mutant mice initially form photoreceptors, but subsequently undergo a progressive retinal degeneration as mice age (24).…”

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confidence: 99%

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Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes

Zhang

Nishimura

Seo

et al. 2011

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

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Bardet-Biedl syndrome (BBS) is a heterogeneous disorder characterized by obesity, retinopathy, polydactyly, and congenital anomalies. The incidence of hypertension and diabetes are also increased in BBS patients. Mutation of 16 genes independently causes BBS, and seven BBS proteins form the BBSome that promotes ciliary membrane elongation. BBS3 (ARL6), an ADP ribosylation factor-like small GTPase, is not part of the BBSome complex. The in vivo function of BBS3 is largely unknown. Here we developed a Bbs3 knockout model and demonstrate that Bbs3 −/− mice develop BBS-associated phenotypes, including retinal degeneration, male infertility, and increased body fat. Interestingly, Bbs3 −/− mice develop some unique phenotypes not seen in other BBS knockout models: no overt obesity, severe hydrocephalus, and elevated blood pressure (shared by some but not all BBS gene knockout mice). We found that endogenous BBS3 and the BBSome physically interact and depend on each other for their ciliary localization. This finding explains the phenotypic similarity between Bbs3 −/− mice and BBSome subunit knockout mice. Loss of Bbs3 does not affect BBSome formation but disrupts normal localization of melanin concentrating hormone receptor 1 to ciliary membranes and affects retrograde transport of Smoothened inside cilia. We also show that the endogenous BBSome and BBS3 associate with membranes and the membrane association of the BBSome and BBS3 are not interdependent. Differences between BBS mouse models suggest nonoverlapping functions to individual BBS protein.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

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Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes

Zhang

Nishimura

Seo

et al. 2011

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

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“…Mutation of BBS genes in mice results in absence of flagella in spermatozoa (8-10) and abnormalities in cilia in brain ependymal cells, airway epithelial cells (11,12) and olfactory neurons (13). At the molecular level, BBS proteins are involved in protein/vesicle trafficking along microtubules.…”

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confidence: 99%

BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly

Seo

Baye²,

Schulz

et al. 2010

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

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Bardet-Biedl syndrome (BBS) is a human genetic disorder resulting in obesity, retinal degeneration, polydactyly, and nephropathy. Recent studies indicate that trafficking defects to the ciliary membrane are involved in this syndrome. Here, we show that a novel complex composed of three chaperonin-like BBS proteins (BBS6, BBS10, and BBS12) and CCT/TRiC family chaperonins mediates BBSome assembly, which transports vesicles to the cilia. Chaperoninlike BBS proteins interact with a subset of BBSome subunits and promote their association with CCT chaperonins. CCT activity is essential for BBSome assembly, and knockdown of CCT chaperonins in zebrafish results in BBS phenotypes. Many disease-causing mutations found in BBS6, BBS10, and BBS12 disrupt interactions among these BBS proteins. Our data demonstrate that BBS6, BBS10, and BBS12 are necessary for BBSome assembly, and that impaired BBSome assembly contributes to the etiology of BBS phenotypes associated with the loss of function of these three BBS genes.Bardet-Biedl Syndrome | ciliopathy | molecular chaperone | protein trafficking T he primary cilium is a microtubule-based subcellular organelle that projects from the surface of the cell. It plays an essential role in the transduction of extracellular signals (1, 2). In vertebrates, loss of cilia or ciliary dysfunction leads to various defects such as situs inversus, polydactyly, neural tube defects, and obesity (2-4). Ciliary dysfunction is also involved in several human genetic syndromes (2, 3). Bardet-Biedl syndrome (BBS) is one of the most studied human genetic disorders associated with ciliary dysfunction. Individuals with BBS display retinal degeneration, obesity, polydactyly, hypertension, hypogonadism, renal anomalies, and cognitive impairment (5-7). BBS displays autosomal recessive inheritance with extensive genetic heterogeneity.BBS proteins are required for the maintenance of ciliary structure and function. Mutation of BBS genes in mice results in absence of flagella in spermatozoa (8-10) and abnormalities in cilia in brain ependymal cells, airway epithelial cells (11,12) and olfactory neurons (13). At the molecular level, BBS proteins are involved in protein/vesicle trafficking along microtubules. For example, knockdown of BBS genes in zebrafish results in delay in retrograde melanosome transport, which is mediated by dynein motor proteins along the microtubule (14, 15). In C. elegans, mutations in bbs1, bbs7, or bbs8 cause defects in the movement of the intraflagellar transport (IFT) subcomplexes inside the cilium (16). During the last decade, twelve BBS genes (BBS1-12) have been identified (17-26). More recently, hypomorphic mutations in two additional genes (MKS1 and CEP290) were reported to be associated with BBS, representing BBS13 and BBS14, respectively (27). Null mutations in MKS1 and CEP290 cause Meckel-Gruber syndrome, a related but more severe disorder (28-30). Seven of the known BBS proteins (BBS1-2, BBS4-5, BBS7-9) have been shown to form a stable complex, the BBSome, and this complex is pr...

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Meckel Syndrome and Related Disorders

Frank¹,

Bergmann²

2013

Encyclopedia of Life Sciences

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Cilia‐related disorders (ciliopathies) are characterised by great clinical and genetic heterogeneity and overlaps between different disease entities. Meckel syndrome (MKS) is generally allelic to Joubert syndrome and related disorders, and resides at the severe end of the broad phenotypic spectrum of ciliopathies. MKS is a usually autosomal recessive, multisystemic disorder of early developmental rather than degenerative nature. Classic disease manifestations comprise occipital meningoencephalocele, cystic kidneys, hepatobiliary ductal plate malformation and postaxial polydactyly, whereas several other additional features such as heart defects and cleft lip/palate have also been reported. Survival beyond birth or the neonatal period is unusual with the vast majority of cases dying in utero. Until recently and before next‐generation sequencing (NGS) have emerged, molecular genetic testing of MKS and related ciliopathies was considerably hampered by its extensive locus heterogeneity. However, NGS‐based technologies make genetic testing now possible and have revolutionised research and diagnostics. For example, specific disease panels that allow sequencing of all disease genes in parallel significantly improve genetic diagnostics and lead to reduction of turnaround times and costs. Key Concepts: Meckel syndrome (MKS) resides at the severe end of the broad phenotypic spectrum of cilia‐related disorders (ciliopathies). MKS and other ciliopathies are clinically and genetically heterogeneous. MKS is a usually autosomal recessive, early developmental multisystemic disorder. Most patients die in utero, survival beyond birth or the neonatal period is unusual. Classic disease manifestations comprise occipital meningoencephalocele, cystic kidneys, hepatobiliary ductal plate malformation and postaxial polydactyly, but additional features are common. At least 10 genes are known for MKS currently, other ciliary genes are thought to be allelic; that is why more than a dozen genes have to be considered to be disease relevant in patients with MKS. Efficient molecular genetic testing of MKS and related disorders have only become feasible with emerging next‐generation sequencing (NGS)‐based approaches. Specific disease panels (e.g. for MKS and related disorders) allow sequencing of all disease genes in parallel and very efficiently lead to reduction of turnaround times and costs.

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Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia

Cited by 107 publications

References 45 publications

Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes

Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes

BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly

Meckel Syndrome and Related Disorders

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