Characterisation of the Frmd7 gene in Idiopathic Infantile Nystagmus using a murine model

Nystagmus is a disorder of the eye characterised by irregular, uncontrolled and repetitive eye movement. It can occur as a secondary condition in a broad spectrum of neurological and ocular disorders or it may occur as an isolated, normally inherited, disorder referred to as idiopathic infantile nystagmus (IIN). Current understanding of ocular-motor control is limited. Similarly, the pathological mechanisms underlying nystagmus are poorly understood. The majority of IIN patients have mutations in the FERM Domain-containing 7 (FRMD7) gene, which was mapped in 2006. The function of Frmd7 is unknown, however, similarity to other FERM domain-containing proteins such as FARP1 and FARP2 suggest its involvement in neuronal outgrowth by modulating the actin cytoskeleton. Current theories on the role of Frmd7 in IIN are contradicting partly due to the lack of Frmd7 murine model, the generation of “knockout-first” conditional Frmd7.tm1a mice by the EUCOMM/KOMP resource offered a useful tool to characterise Frmd7 expression patterns and function. This thesis aims to characterize the function of Frmd7 in IIN using the Frmd7.tm1a mice as a murine model by a combination of molecular, histological and ocular function analysis. The Frmd7.tm1b allele was generated by Cre deletion of the critical exon (exon 4) in the Frmd7.tm1a allele and it was shown to be a more reliable model of Frmd7 knockout at the molecular level. The expression sites of Frmd7 were further investigated using a variety of immunohistochemical techniques such as antibody staining and X-gal staining, and it was shown that Frmd7 expression is restricted to the starburst amacrine cells in the murine retina. Eye tracking recordings of the Frmd7 mutant mice have shown a defect in the horizontal optokinetic reflex which suggests a role of Frmd7 in modulating inhibitory signals of the starburst amacrine cells. The results of this thesis further characterised the role of Frmd7 in IIN using a murine model and established a novel and robust eye tracking technique in mice that can be used in a variety of future studies of nystagmus and other ocular disorders.