LCA is an inherited retinal degenerative disease characterized by reduced vision in infancy. Within the first few months of life, parents usually notice a lack of visual responsiveness and unusual roving eye movements known as nystagmus. LCA typically involves only vision problems, but can be accompanied by disease in other organ systems in a minority of patients. LCA is a common reason children are enrolled in schools for the blind.
"The immediate benefit of this discovery is that affected patients with mutations in this new LCA gene now know the cause of their condition," said Eric Pierce, M.D., Ph.D., co-senior author and director of the Ocular Genomics Institute at Mass. Eye and Ear. "Scientists now have another piece to the puzzle as to why some children are born with LCA and decreased vision. The long-term goal of our research is to develop therapies to limit or prevent vision loss from these disorders."
NMNAT1 is the 18th identified LCA gene. The gene resides in a region that was known to harbor an LCA gene since 2003, but the specific disease gene has been undiscovered until now. These findings will be published on July 29 in the online edition of Nature Genetics.
To identify NMNAT1, scientists performed whole exome sequencing of the family of two siblings who initially presented for evaluation of LCA but who had no mutations in any of the known LCA genes. Being seen by a multi-disciplinary team that took the case from careful clinical characterization to genetic testing to the research laboratory was an essential ingredient for success.
"By using whole exome sequencing, we found a mutation in a gene that no one could have predicted would be associated with LCA," said Dr. Pierce.
"Whereas most of the known LCA genes involve dysfunction of retinal ciliary proteins necessary for light detection in the eye, NMNAT1 is uniquely distinguished by being the first metabolic enzyme linked to LCA," said Marni J. Falk, M.D., co-first author and Clinical Geneticist at The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine.
Having found a mutation in NMNAT1 in this one family, the investigators next asked if mutations in NMNAT1 also cause disease in other patients with LCA. Screening of 284 unrelated patients with LCA from the United States, England, France and India allowed them to identify 13 other patients with mutations in NMNAT1 as the cause of their disease.
Drs. Falk, Pierce and colleagues also studied how the identified mutations in NMNAT1 affect the function of the NMNAT1 protein, and thus may cause dysfunction and death of the light sensitive photoreceptor cells in the retina. Working together with Eiko Nakamaru-Ogiso, Ph.D., in the Department of Biochemistry and Biophysics at The University of Pennsylvania, they found that mutations in NMNAT1 appear to decrease the ability of the NMNAT1 protein to produce NAD+, a key mediator of cellular signaling and energetics.
Early treatment for patients with NMNAT1-related LCA could be especially beneficial.
Researchers found that all but the youngest patient with NMNAT1 mutations had damage to the macula, the center of the retina that is needed for central vision. "This 4-year-old girl who doesn't have central vision loss yet can possibly benefit substantially if we can devise a therapy for her NMNAT1-mediated LCA that prevents her from developing severe central vision loss," Dr. Pierce said.
This study is an example of the multidisciplinary collaboration among the three institutions, using exome sequencing to discover genes involved in inherited diseases caused by mutations of a single gene. "With the robust database and pipeline that we have developed, we have analyzed more than 300 whole exomes of patients and families with single-gene diseases," said Dr. Xiaowu Gai, co-senior author and director of the Center for Biomedical Informatics at Loyola University Chicago Stritch School of Medicine. "We are following up on a number of strong candidate genes. We are sequencing many new samples and expect similar exciting discoveries for other diseases."
About Massachusetts Eye and Ear
Mass. Eye and Ear clinicians and scientists are driven by a mission to find cures for blindness, deafness and diseases of the head and neck. After uniting with Schepens Eye Research Institute in 2011, Mass. Eye and Ear in Boston became the world's largest vision and hearing research center, offering hope and healing to patients everywhere through discovery and innovation. Mass. Eye and Ear is a Harvard Medical School teaching hospital and trains future medical leaders in ophthalmology and otolaryngology, through residency as well as clinical and research fellowships. Internationally acclaimed since its founding in 1824, Mass. Eye and Ear employs full-time, board-certified physicians who offer high-quality and affordable specialty care that ranges from the routine to the very complex. U.S. News & World Report's "Best Hospitals Survey" has consistently ranked the Mass. Eye and Ear Departments of Otolaryngology and Ophthalmology as top five in the nation. Mass. Eye and Ear is home to the Ocular Genomics Institute which aims to translate the promise of personalized genomic medicine into clinical care for ophthalmic disorders. For more information about life-changing care and research, or to learn how you can help, please visit MassEyeAndEar.org.Grant support:
Bacteria as pacemaker for the intestine
22.11.2017 | Christian-Albrechts-Universität zu Kiel
Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
22.11.2017 | Business and Finance
22.11.2017 | Physics and Astronomy
22.11.2017 | Physics and Astronomy