Genetic mutation in HSF4 is associated with retinal degeneration in mice.

Genetic mutations in Hsf4 cause developmental defect of lens at postnatal age. However, the regulatory effect of Hsf4 mutations on retinal homeostasis have not been elucidated. Here we found that HSF4 expresses in retinal and its expression level decrease with age increase. Using Hsf4 mice, which express a Hsf4 mutant with deletion of 42 amino acids in-frame- in the N-terminal hydrophobic region and develop cataracts at P27, we found that Hsf4 mutation downregulated the expression of visual cycle regulatory proteins, RPE65, RDH5 and RLBP1 and heat shock proteins HSP25 and HSP90, but upregulated retinal gliosis and senescence-associated proteins such as cycle-inhibitors P21 and P16 in P10 retina without change retinal structure. With age increase Hsf4 mice undergo retinal degeneration, characterized by thinner ONL, disorganized INL, disconnected RPE, neovascularization, and lipofuscin deposits. ERG results showed that the amplitudes of a- and b-waves at dark adaption were reduced in Hsf4 mice at P15, worsening with age. Intravitreal injection of AAV-Flag-Hsf4b in one-month-old Hsf4 mice partially restored the expression of visual cycle proteins and ERG responses and reduced the gliosis. Studies in vitro indicated that Hsf4 is able to bind to promoters of RPE65 and RDH5. Altogether, these data suggest that Hsf4 participates in regulating the expression of retinal visual cycle-regulatory proteins in addition to heat shock proteins during early retinal development. Genetic mutations in Hsf4 is associated with not only congenital cataracts but also retinal degeneration.