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Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice

Abstract

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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Figure 1: Grm4 mutant mice have normal angle tissues and exhibit high IOP.
Figure 2: Grm4 mutant eyes have short axial length.
Figure 3: Angle closure and choroidal expansion in Grm4 mutant mice.
Figure 4: Grm4 is a serine protease mutation.
Figure 5: Characterization of the PRSS56 protease.
Figure 6: Linkage interval and mutation analysis of PRSS56 in Tunisian families with posterior microphthalmia.

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Acknowledgements

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.

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K.S.N. conceived and executed experiments and participated in study design, data interpretation and manuscript preparation. Z.A. participated in characterization of the protease and maintenance of the mouse strains, genotyping and phenotyping. A.L.K. participated in fine mapping, sequencing of candidate genes, maintenance of mouse strains and histological assessment. I.M.C. contributed to mutant identification, gene mapping and phenotyping. D.G.M. performed physiological experiments. I.S. participated in cell-biology–based experiments. G.R.H. participated in overall design of gene mapping and histological assessment. R.S.S. contributed to histological assessment and interpretation. S.W.M.J. conceived the study, oversaw all aspects of the study and participated in design, conducting experiments, data interpretation and manuscript preparation.

M.H.-A. contributed to experimental design for human families and conducted experiments and participated in data analysis and manuscript preparation. S.B.S. participated in sequencing of human candidate genes. W.B. is an ophthalmologist and performed clinical evaluation of the patients. Z.B. is also an ophthalmologist and performed clinical evaluation of the patients. B.H. participated in human gene sequencing. P.S. provided advice and help with sequencing of some human candidate genes. H.A. oversaw the human study and participated in data analysis.

Corresponding authors

Correspondence to Mounira Hmani-Aifa or Simon W M John.

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The authors declare no competing financial interests.

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Supplementary Table 1, Supplementary Figures 1–6 and Supplementary Note. (PDF 2984 kb)

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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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