Researchers Identify New Gene Causing Blindness
Posted: 02.03.2011
Stephan Zuchner, M.D., Ph.D., Julia Dallman, Ph.D., Margaret A. Pericak-Vance, Ph.D., and, from Bascom Palmer Eye Institute, Byron Lam, M.D., and Rong Wen, Ph.D.
Work was collaborative effort of several departments at the University of Miami
Researchers at the University of Miami Miller School of Medicine have identified a new gene that causes retinitis pigmentosa, a form of blindness, ending one South Florida family’s nearly 20-year search for what caused three of their four children to lose their sight.
The Lidsky children, who are now in their 30s, began to lose their sight in their teens. Their parents, Betti and Carlos, had the family’s DNA tested for more than 50 retinitis pigmentosa (RP) genes. No one found the link until they began working with UM researchers in late 2009. By the summer of 2010, researchers had found the cause of their retinitis pigmentosa using exome sequencing and confirmed it with zebrafish studies.
“For 18 years, we have been searching for the genetic cause of this disease and UM researchers have found it,” Mrs. Lidsky said. “We’ve wanted this for some time. These researchers are truly our heroes. They are doing life-changing work that will benefit not only our family but many other people. We are truly grateful for all their hard work.” The result of the work, a paper titled “Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa,” was published online Thursday, February 3, in the American Journal of Human Genetics. To identify the gene responsible for retinitis pigmentosa in the Lidsky family, researchers used a new technology known as whole exome sequencing, which thoroughly investigates the coding portions of an individual’s genetic material. The RP gene identified in this family codes for an enzyme known as dehydrodolichol diphosphate synthase or DHDDS, which is thought to play a role in how a light-sensing protein named rhodopsin works.
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The research was led by Margaret A. Pericak-Vance, Ph.D., associate dean for human genomic programs, the Dr. John T. Macdonald Foundation Professor of Human Genomics, and director of the John P. Hussman Institute for Human Genomics, along with Stephan Züchner, M.D., Ph.D., first author of the paper and director of the Center for Human Molecular Genomics at the Hussman Institute, and Byron Lam, M.D., professor of ophthalmology at Bascom Palmer Eye Institute.
“This was a powerful demonstration of what we can do with new genetic technologies,” Zuchner said. Important evidence to support this gene as the cause of RP comes from research with zebrafish, led by collaborator Julia Dallman, Ph.D., in the Department of Biology at UM. When researchers in her lab blocked the enzyme, the fish became blind.
Researchers from five areas of the University of Miami — the John P. Hussman Institute for Human Genomics, the Dr. John T. Macdonald Foundation Department of Human Genetics, Bascom Palmer Eye Institute, the Department of Biochemistry and Molecular Biology, and the Department of Biology – worked together to make this exciting discovery. Researchers from the Department of Psychiatry at Mount Sinai School of Medicine and the Center for Human Genetics Research at Vanderbilt University School of Medicine also contributed to the work.
Retinitis pigmentosa refers to a large group of diseases that cause degeneration of the retina of the eye. The retina is located at the back of the eye and its role is to capture light that enters the eye, which is translated into images by the brain. In RP there is damage to the cells in the retina that capture light, known as cones and rods. Over time, these cells slowly stop working and vision deteriorates. One of the first signs of RP is night-blindness, or the slow adaptation to dim light. As RP progresses, people develop tunnel vision, which can eventually lead to a complete loss of vision. RP is diagnosed in approximately 1 in 3,000 to 4,500 people and is known to be caused by changes, or mutations, in many genes.
The Term Paper on Genetic Engineering Human Gene
Genetics will increasingly enable health professionals to identify, treat, and prevent the 4, 000 or more genetic diseases and disorders that our species is heir to. Genetics will become central to diagnosis and treatment, especially in testing for predispositions and in therapies. By 2025, there will likely be thousands of diagnostic procedures and treatments for genetic conditions. Genetic ...
Lam has treated the Lidsky siblings with retinitis pigmentosa – Isaac Lidsky, Daria Zawadzki, and Ilana McGuinn – for several years. He called the RP finding an “exciting discovery.” “Our success in identifying this novel DHDDS gene associated with retinitis pigmentosa demonstrates the power of new genetic methodology to find the cause of disease in small families,” said Lam. “Finding the genetic causes of retinal degeneration is important because it will lead to a better understanding of retinal biology overall.”
“The current findings will encourage further studies designed to examine the role of proteins in the formation and renewal of light-sensitive photoreceptor cells in the retina and how retinitis pigmentosa occurs,” said Eduardo Alfonso, M.D., chair of Bascom Palmer Eye Institute. “The ultimate implications are better patient care and the possibility of developing new therapies.”
While there is no cure for RP at this time, HIHG and Bascom Palmer researchers said the discovery holds promise to develop new avenues for therapy.
This study was supported by grants from the National Institutes of Health (R01-EY012118, P30-EY14801 core grant, R01-EY018586, R01-GM083897, and U54-NS065712), Department of Defense (W81XWH-09-1-0674), Hope for Vision, Research to Prevent Blindness, and a grant from the Florida Office of Tourism, Trade and Economic Development.
http://bascompalmer.org/news/2011/02/um-researchers-identify-new-gene-causing-blindness
Zebra Fish Used to Study Blindness
Published: April 3, 2009 at 12:14 PM
West Layfayette, Ind., April 3 (UPI) — Experiments with zebra fish are helping identify genes linked to retinal diseases that cause blindness, a Purdue University scientist said.
“Once we know the genetic network that influences retinal development, we can begin to understand the changes in specific genes that lead to vision loss,” Yuk Fai Leung said.
With such information, treatments could be developed to prevent or reverse diseases such as macular degeneration and diabetic retinopathy, he said.
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Life starts at conception. Immediately fertilization takes place changes and events occur that will determine the kind of person to be born. This research tries to find out the effect of early life on the later life of an individual. And if early life affects the later life of the individual, then do children who grow up in violent communities have a tendency to exhibit violent behaviors as ...
Using zebra fish, which are closer to humans in eye development than mice or other animal models, a Purdue team developed a new analysis method for analyzing key genes linked to retinal development.
The method can examine thousands of genes and analyze several experimental changes simultaneously, allowing scientists to understand how one change leads to another in degenerative diseases, Leung said.
Retinal degenerative diseases are some of the leading causes of blindness and low vision in an estimated 3.3 million people age 40 and older in the United States, the National Eye Institute said.
http://www.upi.com/Science_News/2009/04/03/Zebra-fish-used-to-study-blindness/UPI-73301238775263
Zebra Fish Sheds Light on Blindness
March 27, 2009
Since Zebrafish eyes contain a mosaic of light-sensitive cells whose structure and functions are nearly identical to those of human eyes, their study may help understand the progression of disease and find more effective treatments for blindness. A study of the retinal development of zebrafish larvae and the genetic switch it has identified should shed new light on the molecular mechanisms underlying that development and, consequently, provide much needed insight on inherited retinal diseases in humans.
Scientists from Florida State University’s (FSU) Department of Biological Science and Program in Neuroscience discovered a gene mutation that determines if the light-sensitive cells develop as rods (the photoreceptors responsible for dim-light vision) or as cones (the photoreceptors needed for color vision).
They are the first to identify the crucial function of a previously known gene called ‘tbx2b’ and have named the newfound allele (a different form of a gene) ‘lor’ – for ‘lots-of-rods’ – because the mutation results in too many rods and fewer ultraviolet cones than in the normal eye.
The team, which includes doctoral candidate Karen Alvarez-Delfin, postdoctoral fellow Ann Morris, and Associate Professor James M. Fadool are excited about the mutation because, ‘it is one of the few mutations in this clinically critical pathway that is responsible for cells developing into one photoreceptor subtype rather than another,‘ said Fadool. The research also produced a number of surprises for the team. The photoreceptor cell changes they observed in the retinas of zebrafish were opposite to the changes identified in Enhanced S-cone syndrome (ESCS), an inherited human retinal dystrophy in which the rods express genes usually only found in cones, eventually leading to blindness. The study also showed that while alterations in photoreceptor development in the human and mouse eyes lead to retinal degeneration and blindness, they don’t in zebrafish. Therefore the team’s work should provide a model for better understanding the differences in outcomes between mammals and fish, and why the human mutation leads to degenerative disease.
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Stem cell research is one of the most interesting areas of biology today. Stem cells have two important characteristics that distinguish them from other types of cells. First, they are unspecialized cells that renew themselves for long periods through cell division. The second is that under certain physiologic or experimental conditions, they can be induced to become cells with special functions, ...
Zebrafish have proved an ideal genetic model for studies as they mature rapidly, lay many eggs and their embryos are transparent and develop externally, unlike mammals, so the developmental process such as the formation of tissues and organs can be studied in living animals. Also they are vertebrates, like humans, and their retinal organization and cell types are similar to those found in humans. The photoreceptors in the fish are arranged in a mosaic, similar to the pattern of a checkerboard but with four colors rather than two alternating in a square pattern. Human retinas have a photoreceptor mosaic, too, but here the term is used loosely, because while the arrangement of the different photoreceptors is nonrandom, they don’t form the geometric pattern observed in zebrafish. The red-, green-, blue-, and ultraviolet-sensitive cones of the zebrafish are always arranged in a precise repeating pattern so mutations causing subtle alterations are easier to uncover using fluorescent labeling and fluorescence microscopes than in retinas with a ‘messier’ arrangement. The research showed that within the mosaic of the lots-of-rod fish, the position on the checkerboard normally occupied by a UV cone is replaced with a rod so the mutated gene can then be identified using a combination of classical genetics and genomic resources.
Morris said, “From a developmental biology perspective, our research will help us unravel the competing signals necessary for generating the different photoreceptor cell types in their appropriate numbers and arrangement,” and, “the highly specialized nature of rods and cones may make them particularly vulnerable to inherited diseases and environmental damage in humans. Understanding the genetic processes of photoreceptor development could lead to clinical treatments for the millions of people affected by photoreceptor cell dystrophies such as retinitis pigmentosa and macular degeneration.” Fish have always been a good source of omega-3 fatty acids, a high intake of which has been linked to healthy eyes. Now it seems our seagoing friends might help our eyesight in another way.
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Circulation Insect adaptations · Insects have an open circulatory system (s) in which blood bathes the tissues directly and does not remain in vessels for an entire circuit (f) · A dorsal heart (s) pumps the haemolymph (f) diagram · Blood flows (f) from posterior to anterior through a tubular heart (s) and anterior to posterior in the body cavity · Blood returns to the heart via valves called ...
The team’s paper (“tbx2b is required for ultraviolet photoreceptor cell specification during zebrafish retinal development”) was published in the Proceedings of the National Academy of Sciences (PNAS).
http://www.gizmag.com/zebrafish-blindness-research/11344/
A microscope image of a zebrafish retina immunolabeled for ultraviolet cones (magenta) and rods (green).
Video:
http://www.sciencecentric.com/news/in_motion_show-09032559.html
Zebrafish study may point way to blindness cure
Wed Aug 1, 2007
(Reuters) – The ability of zebrafish to regenerate damaged retinas has given scientists a clue about restoring human vision and could lead to an experimental treatment for blindness within five years.
British researchers said on Wednesday they had successfully grown in the laboratory a type of adult stem cell found in the eyes of both fish and mammals that develops into neurons in the retina.
In future, these cells could be injected into the eye as a treatment for diseases such as macular degeneration, glaucoma and diabetes-related blindness, according to Astrid Limb of University College London’s (UCL) Institute of Ophthalmology.
Damage to the retina — the part of the eye that sends messages to the brain — is responsible for most cases of sight loss.
“Our findings have enormous potential,” Limb said. “It could help in all diseases where the neurons are damaged, which is basically nearly every disease of the eye.”
Limb and her colleagues studied so-called Mueller glial cells in the eyes of people aged from 18 months to 91 years and found they were able to develop them into all types of neurons found in the retina.
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They were also able to grow them easily in the lab, they reported in the journal Stem Cells.
The cells have already been tested in rats with diseased retinas, where they successfully migrated into the retina and took on the characteristics of the surrounding neurons. Now the team is working on the same approach in humans.
“We very much hope that we could do autologous transplants within five years,” Limb told Reuters.
Autologous transplants, initially on a trial basis, will involve manipulating cells and injecting them back into an individual’s own eye. Eventually, Limb hopes it will also be possible to transfer the cells between different people.
“Because they are so easy to grow, we could make stem cell banks and have cell lines available to the general population, subject to typing as with blood transfusions,” she said.
Just why zebrafish have an abundant supply of adult stem cells to regenerate their retinas, while they are rare in mammals, remains a mystery but Limb suspects it is because mammals have a limiting system to stop proliferation.
The new work on Mueller glial cells is the latest example of researchers exploring the potential of different kinds of stem cells in treating eye disease. Another team from UCL and Moorfield’s Eye Hospital said in June they aimed to repair damaged retinas with cells derived from embryonic stem cells.
http://www.reuters.com/article/2007/08/01/us-blindness-fish-idUSL3139081320070801
Fish Eyes Might Hold Cures to Blindness
Zebrafish Cells Regenerate to Repair Damage
Wednesday, Feb. 16, 2011
What heals the eyes of tiny fish might point the way to helping heal human eyes of damaging diseases that are major causes of blindness, said researchers at Georgia Health Sciences University.
The university held its third annual Vision Discovery Institute Scientific Retreat on Tuesday to review promising research there.
Junko Ariga, a graduate student in the Neuroscience Program at GHSU, presented her work in zebrafish, an animal prized for its replication and regeneration of lost cells.
Working in the lab of Dr. Jeffrey Mumm, who also studies regeneration in zebrafish, Ariga looked at cells known as Müller glial cells that work to keep healthy the retina — the area in the back of the eye responsible for sight. Both mammals and zebrafish have the cells, and they seem to respond to damage in both, but in different ways, Ariga said.
In mammals, it is “like an inflammatory response,” she said. “Whereas in zebrafish, they react more like stem cells and they regenerate all of the retinal cells.”
The response in mammals creates these “huge, sort of nasty scar-like tissues,” Mumm said, but in zebrafish seems to create the cell types needed.
The lab started by looking for hints in literature on potential regeneration in mammals and then looked for the equivalent in zebrafish, Mumm said.
“The main logic there was, if the same pathways are being used in a regenerative manner in both systems, it sort of lends credence to the idea that what we learn about the regenerative regulation in fish will be applicable … hopefully also in humans,” he said.
Ariga might have found that pathway in mammals, Mumm said.
“That was one of the most interesting things about Junko’s most recent work is that one of these molecular pathways that has a limited capacity but nevertheless can enhance regeneration in mammals also appears to be critical for allowing the fish to regenerate at all,” he said.
The work now is to create zebrafish without the pathway, to study the genes involved and potentially use the fish for drug screening, Mumm said. The point of work like this is not just to define the problem but to move beyond it.
“Rather than what it does, we hope to define what it can do,” he said.
http://chronicle.augusta.com/news/health/2011-02-16/fish-eyes-might-hold-cures-blindness
