Fig. 10.

CLDN19 mutations have multiple effects on retinal development. a In the human stem cell model, neurospheres formed, but not optic vesicles or eye cups. Expression was repressed for early eye field transcription factors and many retinal pigment epithelium (RPE)-related genes. Once RPE was established in culture or in mice, the overexpression of claudin mutants led to decreased expression of neurotrophins and RPE65, which led to retinal degeneration and impaired visual function. The loss of RPE65 could be compensated by providing animals with 9-cis-retinal. The solid arrows indicate how correcting the visual cycle can spare vision, but the effects of decreased secretion of neurotrophins by RPE remain to be studied. The dotted arrow indicates that direct effects of claudin-19 on early retinal development are suggested by the study but remain to be explored. b The box suggests a hypothesis whereby a recessive mutation in vivo might lead to a dominant effect when overexpressed. Claudins are known to form complexes, and these are required by claudin-19 to reach the cell surface. Mutant claudin-19 accumulates within the cell and blocks the transport of wild-type claudin-19 from reaching the surface. In heterozygotes, enough wild-type claudin-19 reaches the cell surface to perform its cellular functions (top line). If the mutant is over-expressed, most of the wild-type protein is trapped in internal membranes and the recessive phenotype is observed