Retinal Changes In Idiopathic Infantile Nystagmus Associated With FRMD7 Mutations

Abstract

Purpose: : So far it was postulated that retinal morphology is normal in idiopathic infantile nystagmus (IIN) with or without associated mutations in FRMD7. We investigate the role of FRMD7 in retinal development.

Methods: : In-situ hybridisation (ISH) studies were performed on human and murine embryonic and fetal tissue sections at embryonic stages CS15 (~35dpc) to CS23 (~56dpc) and fetal stage 9 weeks post conception (wpc). Anti-FRMD7antibodies (1:250, Atlas Antibodies) were used for immunohistochemistry (IHC) studies. Primary culture technique was used to culture postnatal day 1 rat retina followed by immunofluorescence using anti-FRMD7 antibodies. Optical Coherence Tomography (OCT) studies were performed in 45 patients with FRMD7 mutations.

Results: : ISH results showed a migratory expression pattern in the developing neural retina between stages CS15 - CS23. Initially expression was restricted to the outer neuroblastic layer (CS15). At the next stage (CS16) we see expression within the inner neuroblastic layer. At 9wpc a bi-laminar expression pattern is seen. IHC studies in murine retina also show the same pattern with strong signals from the developing ganglion cell layers. Moreover, primary culture of the neural retina showed strong FRMD7 expression along the axons and dendrites of neuroblastic cells with no expression in glial cells. OCT studies showed that 12/45 patients with FRMD7 mutations had foveal hypoplasia (defined as a continuation of the inner retinal layers posterior to the foveola). The central macular thickness was significantly thicker in the FRMD7 group when compared to controls. The retinal nerve fibre layer was significantly thinner in patients with FRMD7 mutations when compared to controls.

Conclusions: : This is the first study that highlights the significant role of FRMD7 in retinal development. The retinal expression studies suggest that FRMD7 has a role in migration of retinal cells. Loss of function of FRMD7 can lead to foveal hypoplasia which represents a failure of the centrifugal migration of the inner retinal cells away from the fovea. In addition we describe for the first time retinal nerve fibre layer thinning in patients with FRMD7 mutations, which is consistent with previous in-vitro knockdown assays. Our study shows that IIN related to FRMD7 might be due to afferent defects as seen with other infantile nystagmus forms.

Keywords: nystagmus • retinal development • mutations