Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people1,2,3. Although 4 million people are bilaterally blind from ACG4,5, the causative molecular mechanisms of ACG remain to be defined. High intraocular pressure induces glaucoma in ACG. High intraocular pressure traditionally was suggested to result from the iris blocking or closing the angle of the eye, thereby limiting aqueous humor drainage. Eyes from individuals with ACG often have a modestly decreased axial length, shallow anterior chamber and relatively large lens, features that predispose to angle closure6. Here we show that genetic alteration of a previously unidentified serine protease (PRSS56) alters axial length and causes a mouse phenotype resembling ACG. Mutations affecting this protease also cause a severe decrease of axial length in individuals with posterior microphthalmia. Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG.
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The authors thank A. Bell, S. Kneeland, H. McLaughlin, A. Gillette, M. Ryan, Annette Molbaek, Åsa Schipper and The Jackson Laboratory's Fine Mapping Service and Allele Typing and Sequencing services for technical assistance. We thank P. Nishina for generous use of her OCT and J. Vance of Bioptigen for his expert technical assistance, G. Cox, P. Nishina and M. de Vries for comments on the manuscript and J. Hammer for help with graphics. The National Eye Institute grant EY11721, Barbara and Joseph Cohen Foundation, Ministère de l'Enseignement Supérieur de la Recherche Scientifique et de la Technologie, Tunisia, the Middle East and North Africa region (MENA) (Swedish research links programme supported by the Swedish Research Council (VR)/the Swedish International Development Cooperation Agency (SIDA)) and the Project 2006 planning grant # 348-2005-6336 supported this work. S.W.M.J. is an investigator of the Howard Hughes Medical Institute. We thank the family members for their valuable participation and cooperation.
The authors declare no competing financial interests.
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Nair, K., Hmani-Aifa, M., Ali, Z. et al. Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice. Nat Genet 43, 579–584 (2011). https://doi.org/10.1038/ng.813
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