Retinal dystrophy in Bardet–Biedl syndrome and related syndromic ciliopathies

Mockel, Anaïs; Perdomo, Yaumara; Stutzmann, Fanny; Letsch, J.; Marion, Vincent; Dollfus, Hélène

doi:10.1016/j.preteyeres.2011.03.001

Cited by 143 publications

(118 citation statements)

References 129 publications

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“…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%

“…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. 56 The mTOR signalling inhibitor rapamycin rescues the renal cysts found in BBS zebrafish morphants, implicating the signalling pathways upstream of mTOR in BBS renal pathology.…”

Section: Biology Of the Diseasementioning

confidence: 99%

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Bardet–Biedl syndrome

2012

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Section: Biology Of the Diseasementioning

confidence: 99%

Section: Biology Of the Diseasementioning

confidence: 99%

Bardet–Biedl syndrome

2012

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“…As a consequence, pathological mechanisms of each phenotypic component of BBS, particularly photoreceptor degeneration, are poorly understood. For example, Rho was considered as a BBSome cargo, and Rho mislocalization was suggested as a potential mechanism for photoreceptor degeneration (21), on the basis of the observation that some Rho mislocalizes in old BBS animals (22), the requirement of Rab8 in Rho trafficking (23), and the interaction of the BBSome with Rabin8 [a guanine nucleotide exchange factor (GEF) for Rab8] (13). However, the vast majority of Rho localizes properly to the OS in BBS retinas, indicating that BBS proteins are not essential for Rho trafficking to the OS, and the underlying mechanisms of photoreceptor degeneration remain elusive.…”

Section: Significancementioning

confidence: 99%

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

Datta

Allamargot

Hudson

et al. 2015

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

136

128

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Compartmentalization and polarized protein trafficking are essential for many cellular functions. The photoreceptor outer segment (OS) is a sensory compartment specialized for phototransduction, and it shares many features with primary cilia. As expected, mutations disrupting protein trafficking to cilia often disrupt protein trafficking to the OS and cause photoreceptor degeneration. Bardet-Biedl syndrome (BBS) is one of the ciliopathies associated with defective ciliary trafficking and photoreceptor degeneration. However, precise roles of BBS proteins in photoreceptor cells and the underlying mechanisms of photoreceptor degeneration in BBS are not well understood. Here, we show that accumulation of non-OS proteins in the OS underlies photoreceptor degeneration in BBS. Using a newly developed BBS mouse model [Leucine zipper transcription factor-like 1 (Lztfl1)/Bbs17 mutant], isolated OSs, and quantitative proteomics, we determined 138 proteins that are enriched more than threefold in BBS mutant OS. In contrast, only eight proteins showed a more than threefold reduction. We found striking accumulation of Stx3 and Stxbp1/Munc18-1 and loss of polarized localization of Prom1 within the Lztfl1 and Bbs1 mutant OS. Ultrastructural analysis revealed that large vesicles are formed in the BBS OS, disrupting the lamellar structure of the OS. Our findings suggest that accumulation (and consequent sequestration) of non-OS proteins in the OS is likely the primary cause of photoreceptor degeneration in BBS. Our data also suggest that a major function of BBS proteins in photoreceptors is to transport proteins from the OS to the cell body or to prevent entry of non-OS proteins into the OS.photoreceptor degeneration | trafficking | primary cilia | outer segment | retinitis pigmentosa

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“…This subcellular organelle functions as an antenna, sensing and transducing extracellular signals into the cell, and plays an essential role in regulating multiple cellular processes including the cell cycle, embryonic development, and tissue homeostasis (1)(2)(3). Mutations affecting ciliary and centrosomal components underlie a group of related human disorders such as Joubert syndrome (JBTS), Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP), and Bardet-Biedl syndrome (BBS), collectively termed ciliopathies (1)(2)(3). Recent proteinprotein interaction studies have identified several functional modules or networks involved in these ciliopathies (4).…”

mentioning

confidence: 99%

ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting

Humbert

Weihbrecht

Searby

et al. 2012

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

223

283

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Mutations affecting ciliary components cause a series of related genetic disorders in humans, including nephronophthisis (NPHP), Joubert syndrome (JBTS), Meckel-Gruber syndrome (MKS), and Bardet-Biedl syndrome (BBS), which are collectively termed "ciliopathies." Recent protein-protein interaction studies combined with genetic analyses revealed that ciliopathy-related proteins form several functional networks/modules that build and maintain the primary cilium. However, the precise function of many ciliopathyrelated proteins and the mechanisms by which these proteins are targeted to primary cilia are still not well understood. Here, we describe a protein-protein interaction network of inositol polyphosphate-5-phosphatase E (INPP5E), a prenylated protein associated with JBTS, and its ciliary targeting mechanisms. INPP5E is targeted to the primary cilium through a motif near the C terminus and prenyl-binding protein phosphodiesterase 6D (PDE6D)-dependent mechanisms. Ciliary targeting of INPP5E is facilitated by another JBTS protein, ADP-ribosylation factor-like 13B (ARL13B), but not by ARL2 or ARL3. ARL13B missense mutations that cause JBTS in humans disrupt the ARL13B-INPP5E interaction. We further demonstrate interactions of INPP5E with several ciliary and centrosomal proteins, including a recently identified ciliopathy protein centrosomal protein 164 (CEP164). These findings indicate that ARL13B, INPP5E, PDE6D, and CEP164 form a distinct functional network that is involved in JBTS and NPHP but independent of the ones previously defined by NPHP and MKS proteins.photoreceptor degeneration | retinitis pigmentosa | leber congenital amaurosis | polydactyly | cystic kidney P rimary cilia are microtubule-based cell surface projections that emanate from the centrosome. This subcellular organelle functions as an antenna, sensing and transducing extracellular signals into the cell, and plays an essential role in regulating multiple cellular processes including the cell cycle, embryonic development, and tissue homeostasis (1-3). Mutations affecting ciliary and centrosomal components underlie a group of related human disorders such as Joubert syndrome (JBTS), Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP), and Bardet-Biedl syndrome (BBS), collectively termed ciliopathies (1-3). Recent proteinprotein interaction studies have identified several functional modules or networks involved in these ciliopathies (4). For example, BBS proteins and intraflagellar transport (IFT) proteins form multiprotein complexes, the BBSome and the IFT complexes, respectively, and these complexes are involved in transporting ciliary proteins. Likewise, NPHP and MKS proteins form a distinct modular complex at the transition zone of primary cilia and regulate ciliary membrane compositions (5-9). However, there are many ciliary and centrosomal proteins [e.g., inositol polyphosphate-5-phosphatase E (INPP5E) and ADP-ribosylation factor-like 13B (ARL13B)] that have not been linked to any of the known functional networks and their precise functions ...

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Retinal dystrophy in Bardet–Biedl syndrome and related syndromic ciliopathies

Cited by 143 publications

References 129 publications

Bardet–Biedl syndrome

Bardet–Biedl syndrome

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting

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