GSE176528
Deficiency of the neurodevelopmental disorder-associated gene Cyfip2 alters retinal ganglion cell properties and visual acuity
Intellectual disability (ID) is a neurodevelopmental disorder affecting approximately 0.5-3% of the population in the developed world. Individuals with ID exhibit deficits in intelligence and impaired adaptive behavior, frequently as well as visual impairments. Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is an interacting partner of fragile X mental retardation protein, whose loss results in fragile X syndrome, the most common inherited cause of ID. Recently, CYFIP2 variants were found in patients with early-onset epileptic encephalopathy, developmental delay, and ID. Individuals with these CYFIP2 variants often exhibit visual impairments, however, the underlying mechanism is poorly understood. In the current study, we investigated the role of Cyfip2 in retinal and visual function by generating and analyzing mice in which Cyfip2 is depleted in the retina (Cyfip2 CKO mice). We found no major difference in the layer structure and cell composition between control and Cyfip2 CKO retinas, whereas a subset of genes associated with transporter and channel activity was differentially expressed in the Cyfip2 CKO retina. Multi-electrode array recordings showed more sustained and stronger response to positive flashes of ON ganglion cells in the Cyfip2 CKO retina, although we did not observe that Cyfip2 deficiency affects photoreceptor and ON bipolar cell functions by electroretinogram analysis. Furthermore, initial and late phase OKR analysis demonstrated that Cyfip2 deficiency impairs visual function at the organismal level. Together, our results shed light on the molecular mechanism underlying visual impairments observed in individuals with CYFIP2 variants and, more generally, in patients with neurodevelopmental disorders including ID. Overall design: We performed RNA-sequencing analysis using the control and Cyfip2 CKO retina to assess transcriptional consequences of Cyfip2 deficiency in the retina.