真性小眼球(nanophthalmos),，希臘人稱之為“侏儒眼”,，是一種罕見的因MFRP基因突變導(dǎo)致的眼疾，可導(dǎo)致患者失明,。而MFRP基因有助于控制眼睛的生長并調(diào)節(jié)眼睛的形狀和焦距,。

        美國約翰霍普金斯大學(xué)威爾墨眼科研究所的研究人員通過分析Amish-Mennonite家譜發(fā)現(xiàn)了第一個(gè)導(dǎo)致極端的遠(yuǎn)視的人類基因突變。研究的結(jié)果公布在7月5日的Proceedings  of  the  National  Academy  of  Sciences（PNAS）上,。

        人眼中僅產(chǎn)生少量的MFRP蛋白,，它能改變眼睛的折射或焦距。研究人員希望能夠分析這種蛋白獲得的信息能夠有助于解開“侏儒眼”以及其他形式的遠(yuǎn)視和近視之謎,。

        遠(yuǎn)視和近視源于人類眼睛的復(fù)雜生長過程,。所有的人類眼睛在出生時(shí)都有輕微程度的遠(yuǎn)視。隨著兒童的成長和獲得更多的視覺經(jīng)驗(yàn),，眼睛逐漸通過改變晶狀體和視網(wǎng)膜之間的距離來校正它的焦距,。一旦視網(wǎng)膜處在距離晶狀體的合適的位置并能夠在視網(wǎng)膜上形成適當(dāng)?shù)挠跋窬劢梗罅磕壳拔粗氖褂靡曈X經(jīng)驗(yàn)的機(jī)理就能夠使眼睛停止生長,。由于自然發(fā)生的基因突變使得一些眼睛在到達(dá)這個(gè)點(diǎn)后還繼續(xù)生長,，從而導(dǎo)致近視的發(fā)生。其他一些導(dǎo)致眼睛過早停止生長的突變則引發(fā)近視,。在“侏儒眼”中,，MFRP的一種突變完全搞垮了這個(gè)基因編碼的蛋白質(zhì)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.