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Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice
Zhenglin Yang, … , David S. Williams, Kang Zhang
Zhenglin Yang, … , David S. Williams, Kang Zhang
Published July 24, 2008
Citation Information: J Clin Invest. 2008;118(8):2908-2916. https://doi.org/10.1172/JCI35891.
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Research Article

Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice

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Abstract

Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.

Authors

Zhenglin Yang, Yali Chen, Concepcion Lillo, Jeremy Chien, Zhengya Yu, Michel Michaelides, Martin Klein, Kim A. Howes, Yang Li, Yuuki Kaminoh, Haoyu Chen, Chao Zhao, Yuhong Chen, Youssef Tawfik Al-Sheikh, Goutam Karan, Denis Corbeil, Pascal Escher, Shin Kamaya, Chunmei Li, Samantha Johnson, Jeanne M. Frederick, Yu Zhao, Changguan Wang, D. Joshua Cameron, Wieland B. Huttner, Daniel F. Schorderet, Frances L. Munier, Anthony T. Moore, David G. Birch, Wolfgang Baehr, David M. Hunt, David S. Williams, Kang Zhang

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Figure 2

Electron microscopy of PROM1 transgenic mouse rod photoreceptors.

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Electron microscopy of PROM1 transgenic mouse rod photoreceptors.
   
(A...
(A and B) Overgrown and abnormally oriented disk membranes (arrows) in PMT3 retinas were visible at 16 days (A) and 4 months (B) of age. Arrowheads indicate vesiculated membrane. Higher-magnification view of the boxed region in B is shown in the inset. (C) Electron micrograph showing abnormalities in the RPE of PMT3 mice at 4 months of age. Accumulation of lipofuscin-like material (arrows) was evident. (D) Electron micrograph of a WT retina, showing normal OS disk membranes and adjacent RPE. Scale bars: 1 μm (A, B, and D); 300 nm (C); 30 nm (B, inset).
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