Glaucoma-causing Myocilin mutational landscape in Olfactomedin 1 suggests protein aggregation mediated retinal ganglion cell insults in the eye

Authors

• D Kumar
• P Johnson
• N Nakaya
• SI Tomarev

Abstract

Olfactomedin (OLFM) domain-containing proteins including MYOCILIN (MYOC) and OLFM1/2/3 are of great importance in the pathophysiology of glaucoma and other eye diseases. In the eye, MYOC is expressed in angle tissues, while OLFM1/2/3 are actively expressed in retinal ganglion cells (RGCs) and are constituents of the functional AMPA receptor complex. Changes in the composition and properties of this complex may lead to RGC death. Since the OLFM domain is conserved in these proteins, we explored the impact of reported glaucoma-causing MYOC mutations in the OLFM domain of OLFM1 in order to reveal their functional consequences in RGC insult and the possible mechanism of AMPA receptor mediated RGCs death in glaucoma. We identified 182 glaucoma-causing MYOC mutations. Among them, only 27 were pathogenic, while others had uncertain clinical-significance. Amidst all conserved mutation-sites, we reported 9 spatially conserved glaucoma-causing MYOC mutations at their homologous sites in OLFM1. Four of these MYOC mutations R296H, D380N, E385K, and Q424H were predicted as deleterious, while G246R, R296C, and G434S as likely-deleterious in OLFM1. Interestingly, these conserved mutations were reported at or in close-vicinity of Aβ42 (D380N, E385K, G434S), Tau (Q424H, G434S, T438I), and α-Synuclein (G246R, Q424H, G434S) fibrillogenic sites. Structural mapping revealed the presence of these spatially conserved mutations and aggregation prone residues mostly on the surface of OLFM1 that may affect its interaction with other proteins. Overall, our study suggests that spatially conserved MYOC mutations associated with glaucoma in OLFM1 may adversely affect the fibrillogenesis of OLFM1, potentially impairing its interaction with AMPA receptors.

Scientific Focus Area: Computational Biology

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