Researchers Discover New Gene Linked to Cone and Cone-Rod Dystrophies

July 31, 2014

Foundation-funded researchers at the Radboud University Medical Center in the Netherlands have found that mutations in the gene POC1B can cause cone dystrophy (COD) and cone-rod dystrophy (CRD). These retinal degenerative conditions are characterized by progressive loss of central vision, with CRD also leading to peripheral vision loss. The discovery of harmful defects in POC1B will help scientists diagnose more patients and identify targets for vision-saving therapies. Results of the study were published in The American Journal of Human Genetics.

The researchers used whole-exome sequencing (WES) to search for the disease-causing gene in affected families. The state-of-the-art approach involves targeting the exome, the regions in a person’s DNA that are most likely to harbor harmful mutations. The exome contains the code for making proteins essential to the health and function of cells, including those of the retina.

More than three billion “letters” make up a person’s DNA. The exome is only 1.5 percent of those letters, providing a relatively narrow target for finding genetic defects. Ultimately, the Radboud scientists found POC1B mutations in three siblings from a Turkish family as well as a Dutch individual.   

Prior to the advent of WES four years ago, studies to find new, disease-causing genes took considerably more time, were more frequently unsuccessful and required larger numbers of affected individuals and families.

“Advanced gene-sequencing technologies are greatly accelerating the discovery of new retinal-disease genes,” says Stephen Rose, Ph.D., chief research officer at the Foundation Fighting Blindness. “Each new discovery adds another piece to the large retinal-disease puzzle and moves us closer to treatments and cures.” More than two dozen genes have been linked to COD and CRD.

The investigators learned more about POC1B’s role in the retina by turning the gene off in zebrafish during their development. The resulting fish had shorter-than-normal photoreceptors and did not respond to a visual stimulus.

“This advancement would not have been possible without collaborating experts from diverse fields — including genetics, cell biology and zebrafish modeling — to identify and confirm the rare causes of these vision impairments,” says Frans Cremers, Ph.D., a genetic researcher involved in the study. Anneke den Hollander, Ph.D., and Susanne Roosing also participated in the genetic research. Ronald Roepman, Ph.D., and Ideke Lamers provided expertise in cell biology. Erik de Vrieze, Ph.D., and Erwin van Wijk, Ph.D., conducted the zebrafish studies.

COD, CRD and other retinal degenerations that affect cones can be particularly difficult for vision, because cones are the photoreceptors that enable people to read, recognize faces, drive and see in lighted conditions. Rods provide night and peripheral vision.

Mutations in POC1B can cause autosomal recessive forms of the condition, meaning it was inherited from parents who carry the disease but are not affected. Their children have a one-in-four chance of getting the condition.

FFB provides nearly $1.8 million in funding for genetic, imaging and protein studies at Radboud University.