RGD Reference Report - Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome. - Rat Genome Database

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

Authors: Datta, P  Allamargot, C  Hudson, JS  Andersen, EK  Bhattarai, S  Drack, AV  Sheffield, VC  Seo, S 
Citation: Datta P, etal., Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4400-9. doi: 10.1073/pnas.1510111112. Epub 2015 Jul 27.
RGD ID: 11532386
Pubmed: PMID:26216965   (View Abstract at PubMed)
PMCID: PMC4538681   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1510111112   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Bardet-Biedl syndrome 1  ISOStx3 (Mus musculus)11532386; 11532386 RGD 
Bardet-Biedl syndrome 1  ISOStxbp1 (Mus musculus)11532386; 11532386 RGD 
Bardet-Biedl syndrome 1  IEP 11532386; 11532386 RGD 
Bardet-Biedl syndrome 17  ISOStx3 (Mus musculus)11532386; 11532386protein:increased expression:photoreceptor outer segment layer RGD 
Bardet-Biedl syndrome 17  ISOStxbp1 (Mus musculus)11532386; 11532386protein:increased expression:photoreceptor outer segment layer RGD 
Bardet-Biedl syndrome 17  IEP 11532386; 11532386protein:increased expression:photoreceptor outer segment layer RGD 

Objects Annotated

Genes (Rattus norvegicus)
Stx3  (syntaxin 3)
Stxbp1  (syntaxin binding protein 1)

Genes (Mus musculus)
Stx3  (syntaxin 3)
Stxbp1  (syntaxin binding protein 1)

Genes (Homo sapiens)
STX3  (syntaxin 3)
STXBP1  (syntaxin binding protein 1)


Additional Information