Disruption of intraflagellar protein transport in photoreceptor cilia is associated with childhood blindness

RHO

Researchers from the department of Human Genetics in Nijmegen have discovered that a specific kind of very early-onset childhood blindness, Leber congenital amaurosis (LCA), can be caused by disruption of the protein transport machinery in the photoreceptor cells of the retina. By using a new quantitative affinity proteomics approach, they were able to identify which exact part of this mechanism was disrupted in patients that suffer from this inherited disease. This study was recently published in the Journal of Clinical Investigation

A close collaboration of the Ciliopathy research group of Ronald Roepman (NCMLS, RUNMC) with scientists from the Institute of Ophthalmic Research in Tuebingen (Germany), and the Jackson Laboratory (USA) enabled an integral analysis of the molecular disease mechanism of LCA5. They used stable isotope labeling of amino acids in cell culture (SILAC) to show that LCA5-encoded lebercilin specifically binds to the intraflagellar transport (IFT) machinery. This machinery essentially regulates protein transport in primary cilia, small finger-like protrusions of the cell membrane that exert important sensory signalling functions. The interaction with the IFT machinery disappeared when two human LCA-associated lebercilin mutations were introduced, implicating that a specific disruption of IFT-dependent protein transport in the cilia of the photoreceptors, the opsin-loaded outer segments, leads to this disease. Lca5 inactivation in mice led to partial displacement of rhodopsin (see: image) and light-induced translocation of arrestin from photoreceptor outer segments of the retina. This was consistent with a defect in IFT at the connecting cilium, leading to failure of proper outer segment formation and subsequent photoreceptor degeneration. These data suggest that lebercilin functions as a key element of selective protein transport through photoreceptor cilia and provide a molecular demonstration that disrupted IFT can lead to LCA.

Boldt K*, Mans DA*, Won J*, van Reeuwijk J, Vogt A, Kinkl N, Letteboer SJ, Hicks WL, Hurd RE, Naggert JK, Texier Y, den Hollander AI, Koenekoop RK, Bennett J, Cremers FP, Gloeckner CJ, Nishina PM, Roepman R#, Ueffing M#. *, # Equal contributions. Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice. J Clin Invest. 2011 Jun 1;121(6):2169-80. PMID: 21606596.







Reference:

Boldt K*, Mans DA*, Won J*, van Reeuwijk J, Vogt A, Kinkl N, Letteboer SJ, Hicks WL, Hurd RE, Naggert JK, Texier Y, den Hollander AI, Koenekoop RK, Bennett J, Cremers FP, Gloeckner CJ, Nishina PM, Roepman R#, Ueffing M#. *, # Equal contributions. Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice. J Clin Invest. 2011 Jun 1;121(6):2169-80. PMID: 21606596.


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