Scientists examined how changes in a gene known as Retinitis Pigmentosa GTPase Regulator (RPGR) damage eye cells to cause a disorder known as X-linked retinitis pigmentosa. The condition is incurable and affects night and peripheral vision before gradually causing blindness in middle age.
Researchers took skin samples from two patients and transformed stem cells - which can change into any cell type - into light-sensing eye cells known as photoreceptors. They compared these with cells from healthy relatives of the patients.
Photoreceptors - which decay in retinitis pigmentosa patients - differed in their fundamental structure when compared with those from family members. Authors show that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments.
Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation.
Follow-up studies in mice identified key molecules that interact with RPGR to maintain the structure of photoreceptors. When RPGR is flawed, the structure is compromised and photoreceptors cannot function correctly, leading to sight loss.
Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors.
These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.
The study lead, said: "By furthering our understanding of the RPGR gene and its effects on photoreceptor cells, we hope our findings bring us closer to developing a possible treatment for this devastating disease."