真性小眼球(nanophthalmos)，希腊人称之为“侏儒眼”，是一种罕见的因MFRP基因突变导致的眼疾，可导致患者失明。而MFRP基因有助于控制眼睛的生长并调节眼睛的形状和焦距。
美国约翰霍普金斯大学威尔墨眼科研究所的研究人员通过分析Amish-Mennonite家谱发现了第一个导致极端的远视的人类基因突变。研究的结果公布在7月5日的Proceedings of the National Academy of Sciences（PNAS）上。
人眼中仅产生少量的MFRP蛋白，它能改变眼睛的折射或焦距。研究人员希望能够分析这种蛋白获得的信息能够有助于解开“侏儒眼”以及其他形式的远视和近视之谜。
远视和近视源于人类眼睛的复杂生长过程。所有的人类眼睛在出生时都有轻微程度的远视。随着儿童的成长和获得更多的视觉经验，眼睛逐渐通过改变晶状体和视网膜之间的距离来校正它的焦距。一旦视网膜处在距离晶状体的合适的位置并能够在视网膜上形成适当的影像聚焦，大量目前未知的使用视觉经验的机理就能够使眼睛停止生长。由于自然发生的基因突变使得一些眼睛在到达这个点后还继续生长，从而导致近视的发生。其他一些导致眼睛过早停止生长的突变则引发近视。在“侏儒眼”中，MFRP的一种突变完全搞垮了这个基因编码的蛋白质的功能.
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, or "dwarf eye," a rare, potentially blinding disorder, is 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.
Authors of the study are Sundin, Gregory Leppert, Eduardo Silva, Jun-Ming Yang, Sharola Dharmaraj, Irene Maumenee, Jeffrey Toy, Ethan Weinberg, Cameron Parsa, Karl Broman, Cathy DiBernardo and Janet Sunness of Johns Hopkins; Elias Traboulsi of the Cole Eye Clinic, Cleveland Clinic Foundation, Cleveland, Ohio; and Luisa Coutinho Santos of the Lisbon Institute of Ophthalmology in Portugal.
Gregory Leppert is currently at the National Institutes of Health/Foundation for Advanced Education in the Sciences, Bethesda, Md.; Jun-Ming Yang at the National Institutes of Health/National Cancer Institute, Bethesda; Sharola Dharmaraj at the Massachusetts Eye and Ear Infirmary, Mass.; Janet Sunness at the Department of Ophthalmology in the Greater Baltimore Medical Center, Towson, Md.; and Jeffrey Toy at the Food and Drug Administration, Rockville, Md.
The research was supported by the National Institutes of Health, a Wasserman award from Research to Prevent Blindness, the Knights Templar Eye Foundation, the Wilmer Eye Institute, and the Portuguese Foundation for Science and Technology.
PNAS July 5, 2005; 102(27):9553-9558.
On the Web:
http://www.pnas.org/cgi/content/abstract/102/27/9553
Nanophthalmos
A very small but otherwise normal eye. All the eye structures are proportionately small as well. This condition is associated with extreme farsightedness.
