Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Massachusetts Eye and Ear researchers discover elusive gene that causes a form of blindness from birth

30.07.2012
Researchers from the Massachusetts Eye and Ear Infirmary, The Children's Hospital of Philadelphia, Loyola University Chicago Health Sciences Division and their collaborators have isolated an elusive human gene that causes a common form of Leber congenital amaurosis (LCA), a relatively rare but devastating form of early-onset blindness. The new LCA gene is called NMNAT1. Finding the specific gene mutated in patients with LCA is the first step towards developing sight-saving gene therapy.

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:
This work was supported by grants from the National Institutes of Health [RO1-EY12910 (E.A.P.), R03-DK082446 (M.J.F.), R01-GM097409 (E.N-O), P30HD026979 (M.J.F.,R.X.) and P30EY014104 (MEEI core support)]; the Foundation Fighting Blindness USA (I.A.,A.D.B.,E.L.B.,S.S.B.,Q.L.,A.T.M., D.S.M.,E.A.P., J-A.S.,S.M-S., A.R.W.); Rosanne Silbermann Foundation (E.A.P.); Penn Genome Frontiers Institute (E.A.P, X.G.); Institutional Fund to the Center for Biomedical Informatics by the Loyola University Stritch School of Medicine (X.G.); the Foerderer Award for Excellence from the Children's Hospital of Philadelphia (M.J.F. and X.G.); The Angelina Foundation Fund from the Division of Child Development and Metabolic Disease at The Children's Hospital of Philadelphia (M.J.F.); The Clinical and Translational Research Center at The Children's Hospital of Philadelphia (UL1-RR-024134) (M.J.F. and E.A.P.); the Department of Biotechnology, Government of India and the Champalimaud Foundation, Portugal (C.K); the Hyderabad Eye Research Foundation (C.K.); a senior research fellowship from the Council for Scientific and Industrial Research (R.S.); Foundation Voir et Entendre (C.Z.), Ville de Paris and Région Ille de France; RP Fighting Blindness (UK)(A.R.W.), Fight For Sight (UK) (A.D.B.,S.S.B.,A.T.M., D.S.M.,A.R.W.), Moorfields Eye Hospital NIHR BRC for Ophthalmology (A.D.B.,S.S.B.,A.T.M.,D.S.M.,A.R.W.), Special Trustees of Moorfields Eye Hospital (A.D.B., S.S.B.,A.T.M.,D.S.M.,A.R.W.).

Mary Leach | EurekAlert!
Further information:
http://www.harvard.edu
http://www.MassEyeAndEar.org

More articles from Life Sciences:

nachricht Solving the efficiency of Gram-negative bacteria
22.03.2019 | Harvard University

nachricht Bacteria bide their time when antibiotics attack
22.03.2019 | Rice University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The taming of the light screw

DESY and MPSD scientists create high-order harmonics from solids with controlled polarization states, taking advantage of both crystal symmetry and attosecond electronic dynamics. The newly demonstrated technique might find intriguing applications in petahertz electronics and for spectroscopic studies of novel quantum materials.

The nonlinear process of high-order harmonic generation (HHG) in gases is one of the cornerstones of attosecond science (an attosecond is a billionth of a...

Im Focus: Magnetic micro-boats

Nano- and microtechnology are promising candidates not only for medical applications such as drug delivery but also for the creation of little robots or flexible integrated sensors. Scientists from the Max Planck Institute for Polymer Research (MPI-P) have created magnetic microparticles, with a newly developed method, that could pave the way for building micro-motors or guiding drugs in the human body to a target, like a tumor. The preparation of such structures as well as their remote-control can be regulated using magnetic fields and therefore can find application in an array of domains.

The magnetic properties of a material control how this material responds to the presence of a magnetic field. Iron oxide is the main component of rust but also...

Im Focus: Self-healing coating made of corn starch makes small scratches disappear through heat

Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.

Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...

Im Focus: Stellar cartography

The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.

A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...

Im Focus: Heading towards a tsunami of light

Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.

"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

International Modelica Conference with 330 visitors from 21 countries at OTH Regensburg

11.03.2019 | Event News

Selection Completed: 580 Young Scientists from 88 Countries at the Lindau Nobel Laureate Meeting

01.03.2019 | Event News

LightMAT 2019 – 3rd International Conference on Light Materials – Science and Technology

28.02.2019 | Event News

 
Latest News

Solving the efficiency of Gram-negative bacteria

22.03.2019 | Life Sciences

Bacteria bide their time when antibiotics attack

22.03.2019 | Life Sciences

Open source software helps researchers extract key insights from huge sensor datasets

22.03.2019 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>