Researchers discover elusive gene that causes Leber congenital amaurosis

July 29, 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 known as nystagmus. LCA typically involves only vision problems, but can be accompanied by disease in other in a minority of . 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 has been undiscovered until now. These findings will be published on July 29 in the online edition of .

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 . "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 ," 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 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 . We are sequencing many new samples and expect similar exciting discoveries for other diseases."

Explore further: Sustained safety, efficacy of gene therapy for inherited retinal disease

More information: DOI: 10.1038/ng.2356 , DOI: 10.1038/ng.2357 , DOI: 10.1038/ng.2361 , DOI: 10.1038/ng.2370

Related Stories

Sustained safety, efficacy of gene therapy for inherited retinal disease

September 19, 2011
Three years ago, preliminary but encouraging results were announced regarding the safety and success of gene therapy in a small cohort of patients with an inherited form of blindness known as Leber congenital amaurosis (LCA).  ...

Recommended for you

A rogue gene is causing seizures in babies—here's how scientists wants to stop it

July 26, 2017
Two rare diseases caused by a malfunctioning gene that triggers seizures or involuntary movements in children as early as a few days old have left scientists searching for answers and better treatment options.

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.