Zebrafish reveal wider role for gene linked to human albinism

VANCOUVER, Wash. — Tiny, striped zebrafish are helping scientists trace how a gene linked to albinism influences eye development, work that may ultimately help explain some of the vision problems experienced by people with the condition and guide the search for new treatments.

In a study published in Developmental Biology, Washington State University researchers found that mutations in OCA2, a gene responsible for one of the most common forms of albinism, caused unexpected changes in pigment cells, eye formation and the activity of dozens of other genes in zebrafish embryos.

The findings suggest OCA2 may play a wider role in development beyond helping produce melanin, the pigment that gives color to the skin, hair and eyes. If similar processes occur in humans, the research could eventually help explain complications associated with albinism, including impaired vision and involuntary eye movement.

“We’re interested in understanding processes that you wouldn’t necessarily expect to depend on melanin, but it turns out they do,” said corresponding author Cynthia Cooper, a professor in WSU’s School of Molecular Biosciences at WSU Vancouver. “It’s another surprising mechanism that cells are using to develop correctly.”

Small fish, big scientific role

Scientists have used zebrafish to investigate genetics and development for more than five decades, studying everything from heart development to neurological disorders and cancer. Cooper has worked with the fish for more than 20 years.

Like people, zebrafish are vertebrates and use many of the same genes to produce pigment cells. Their transparent embryos also develop quickly outside the body, allowing scientists to observe biological changes that would be difficult to study in humans.

For the new study, Cooper and her colleagues examined embryos carrying a mutation in the zebrafish version of the OCA2 gene. They tracked how pigment cells and the eyes developed, then compared gene activity in embryos carrying the mutation with embryos that did not carry it.

The researchers found unexpected differences in the number and location of iridophores, reflective pigment cells found in fish and amphibians. People do not have iridophores, but the cells arise from neural crest cells, which also give rise to several types of human cells. That makes them a useful window into how a mutation in a pigment-related gene can affect cell development.

The team also found changes in the developing eyes. A temporary opening in the embryonic eye took longer than usual to close, while cells in the retina developed and organized differently.

When researchers compared gene activity in embryos with and without the mutation, they identified changes in dozens of genes, including many that help cells determine what they will become and guide the formation of the eyes and other tissues.

Together, the results suggest OCA2 may influence development in ways that go beyond its established role in producing melanin.

The findings cannot yet be assumed to apply directly to people. Cooper said researchers will need to determine where, when and why the altered gene activity occurs, then look for similar effects in mammals and, eventually, human cells.

Albinism affects an estimated one in 17,000 people worldwide, although prevalence varies widely among populations. Visual problems are a defining feature of the condition and can create lifelong challenges with everyday activities such as reading and driving.

By revealing more about how the condition affects development, the research could eventually help researchers identify possible treatment targets for vision complications associated with albinism. Cooper said a clearer understanding of normal cell development could also inform research into diseases such as cancer, in which cells fail to develop or behave normally.

The research also provided hands-on experience for WSU Vancouver students. Co-authors J. Rionach McCarthy and Samuel Vernon were undergraduates when they conducted their experiments, continuing a tradition in Cooper’s lab that has helped prepare about 60 students for careers in medicine, pharmacy and research.

“We’re just trying to figure out what it is about this gene that is causing changes to the activation of genes in neighboring cells,” Cooper said. “That’s what we’re up to next.”