First human gene mutation that causes extreme farsightedness

Working with an Amish-Mennonite family tree, Johns Hopkins researchers at the Wilmer Eye Institute have discovered what appears to be the first human gene mutation that causes extreme farsightedness.

The researchers report that nanophthalmos, Greek for "dwarf eye," is a rare, potentially blinding disorder caused by an alteration in a gene called MFRP that helps control eye growth and regulates the organ's shape and focus. The study is described in the July 5 issue of the Proceedings of the National Academy of Sciences.

"The MFRP protein is only made in a tiny portion of the human eye, and it can alter eye refraction, or focus," said Olof Sundin, Ph.D., assistant professor of ophthalmology at the Johns Hopkins School of Medicine in the Wilmer Eye Institute. "We hope this protein holds the key to unlocking not only nanophthalmos, but other forms of farsightedness and nearsightedness as well."

Hyperopia (farsightedness) and myopia (nearsightedness) -- the ability to see only distant or near objects clearly, respectively -- stems from the complex growth of the human eye. All human eyes have a slight degree of farsightedness at birth. As the child grows and gains more visual experience, the eye adjusts its focus by growing, which changes the distance between the lens and the retina, the light-detecting layer of cells at the back of the eye. Once the retina is the right distance from the lens for proper focus of images on the retina, a largely unknown mechanism that uses visual experience causes the eye to stop growing.

Due to natural genetic mutations, some eyes continue to grow beyond this point, causing nearsightedness. Other mutations cause the eye to stop growing too soon, causing farsightedness. In the case of nanophthalmos, a mutation in MFRP completely wipes out the function of the protein coded for by the gene. In people with this condition, the retina is too close to the lens, but the lens and cornea, the eye's outermost layer, are of normal size and shape.

"Eyes with nanophthalmos still work quite well, despite these complications," said Sundin. "But the disease's secondary complications later in life, including glaucoma or detached retina, are far more severe and can lead to complete blindness."

One such patient with nanophthalmos, an Amish-Mennonite woman who was blind in one eye, came to the Wilmer Eye Institute in 1998 for treatment. By reconstructing the woman's family tree, the researchers discovered that several living relatives also suffered from nanophthalmos, and four deceased relatives had been part of the classic Johns Hopkins Bloomberg School of Public Health study in the 1970s that helped define the disease as genetic.

In Sundin's study, the researchers examined the woman's DNA for possible gene mutations causing nanophthalmos. According to Sundin, MFRP was a surprise candidate.

"Mutant MFRP was recently identified in mice as a cause of retinal degeneration, not extreme farsightedness," he said. "However, a mouse's eyes do not adjust their focus through growth like human eyes do, so MFRP has a completely different function in mice and was not assumed to alter eye refraction in humans."

The research team successfully mapped the MFRP gene mutation in humans and discovered that the protein was completely missing from nanophthalmos patients.

In a normal human eye, the MFRP protein is located on the surface of the retinal pigment epithelium (RPE), which is located beneath the retina and helps maintain photoreceptors, the eye's light-detecting cells. Blindness occurs when these cells die after detachment of the retina from the RPE.

Beneath the RPE are two layers of structural tissue that give the eye its shape. During childhood, these tissues stretch, like a balloon, as the eye grows. "The RPE is believed to be the key link in signaling these tissues to stretch," said Sundin. "And MFRP, located exclusively in the RPE and nowhere else in the body, is likely involved in that signaling process."

Sundin plans to further investigate MFRP and ultimately develop drugs to regulate the gene's function. He hopes the information gained from his study will open doors to correcting other types of severe refractive error, not only farsightedness, but also nearsightedness.

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