Exome sequencing identifies mutations in<i>LZTFL1</i>, a BBSome and smoothened trafficking regulator, in a family with Bardet–Biedl syndrome with situs inversus and insertional polydactyly

Marion, Vincent; Stutzmann, Fanny; Gérard, Marion; Melo, Charlie De; Schaefer, Eric; Claussmann, Aurélie; Hellé, Sophie; Delague, Valérie; Souied, Eric H.; Barrey, Catherine; Verloes, Alain; Stoetzel, Corinne; Dollfus, Hélène

doi:10.1136/jmedgenet-2012-100737

Cited by 120 publications

(107 citation statements)

References 22 publications

(17 reference statements)

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“…LZTFL1 mutations were then found in human patients with BBS, rendering it the 17th BBS gene (BBS17) (24,25). More recently, it was shown that Lztfl1 cycles between cilia and the cytoplasm and facilitates removal of the BBSome from cilia (26).…”

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.

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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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.

128

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“…BBS is a genetically heterogeneous condition for which 19 BBS14/CEP290, BBS15/WDPCP/FRITZ, BBS16/SDCCAG8, BBS17/LZTFL1, BBS18/BBIP10/BBIP1 and BBS19/IFT27; ( [9][10][11][12][13][14] and references within). This heterogeneity was originally thought to be the cause of the significant inter-familial variability that characterizes the syndrome.…”

Section: The Genetics Of Bbsmentioning

confidence: 99%

Bardet–Biedl syndrome: Is it only cilia dysfunction?

et al. 2015

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a b s t r a c tBardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic disorder, characterized by both congenital and late onset defects. From the analysis of the mutational burden in patients to the functional characterization of the BBS proteins, this syndrome has become a model for both understanding oligogenic patterns of inheritance and the biology of a particular cellular organelle: the primary cilium. Here we briefly review the genetics of BBS to then focus on the function of the BBS proteins, not only in the context of the cilium but also highlighting potential extra-ciliary roles that could be relevant to the etiology of the disorder. Finally, we provide an overview of how the study of this rare syndrome has contributed to the understanding of cilia biology and how this knowledge has informed on the cellular basis of different clinical manifestations that characterize BBS and the ciliopathies.

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“…140 Many BBS proteins have been shown to localize to the photoreceptors, [140][141][142][143] and loss of most of the BBSome proteins leads to retinal degeneration in model organisms and humans as part of the multi-organ condition Bardet-Biedl syndrome (BBS). 141,[144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159] For example, Bbs1 knock-in mutant mice develop disorganized OS, and exhibit degeneration of IS and OS. 160 Other work has exemplified the disease mechanism of disrupted trafficking that underlies the retinal degeneration in this ciliopathy.…”

mentioning

confidence: 99%