A novel OPHN1 variant results in a mild form of OPHN1 syndrome characterized by cyclic strabismus

Abstract Individuals with cyclic strabismus experience the disease in a pattern in which days with or without strabismus alternate in a circadian rhythm-dependent manner. However, the molecular mechanism that underlies this rhythm is unknown. In this study, we link cyclic strabismus to a novel hemizygous variant of the OPHN1 gene, which encodes a Rho GAP protein, and mutations of which are known cause strabismus. Interestingly, this novel K306N variant affected the PH domain of OPHN1 and enhanced its ability to bind to the phosphatidylinositol phosphates (PIPs) PI4P and PI5P. Our work indicates that at least some cases of cyclic strabismus are due to a gain-of-function variant of OPHN1. We propose that this alteration may change the subcellular localization of the OPHN1 Rho GAP protein such that its normal activity in an appropriate site is reduced, leading to cyclic strabismus.