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

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 1

Retinal degeneration as a consequence of mutant PROM1.

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Retinal degeneration as a consequence of mutant PROM1. (A and B) Cli...
(A and B) Clinical features of autosomal-dominant macular dystrophy and segregation of a PROM1 mutation. (A) Left: Fundus photograph from a STGD4 patient with visual acuity of 20/200, showing an area of macular atrophy with surrounding yellow flecks (white arrows). Right: Fundus photograph from an MCDR2 patient with a visual acuity of 20/80, showing bull’s-eye maculopathy (white arrows). (B) Sequencing traces demonstrating an 1117 C>T transition in exon 10 giving rise to the missense R373C substitution in both families. (C) Fundus photographs from representative 12-month-old PTW20 (left), 4-month-old PMT14 (middle), and 13-month-old PMT14 (right) mice. Yellow arrows denote yellow deposits and small lesions scattered throughout the central fundus. Black arrows denote large coalescing deposits and atrophic lesions in the fundus. (D) Progressive photoreceptor loss, as determined by the number of nuclei in the ONL, in PMT3 and PMT14 mice compared with normal C57BL/6 (control) and PWT20 mice. Photoreceptor cell nuclei were counted in transgenic mice between 4 and 40 weeks of age. Error bars, which in most cases are too small to be visible, represent ± SEM. The rate of photoreceptor cell loss was greater in the PMT14 line, which expressed higher levels of mutant PROM1 than did PMT3 mice (see Figure 3).