Sequencing uncovers new cause of inherited childhood blindness

A mutation in a gene called NMNAT1 can cause a form of inherited childhood blindness called Leber congenital amaurosis, said researchers, including those from Baylor College of Medicine, in four reports that appear online today in the journal Nature Genetics.

"The normal function of this gene is one of the things that makes this finding exciting," said Dr. Rui Chen, associate professor in the Baylor College of Medicine Human Genome Sequencing Center and a corresponding author of the report that involved a consortium of scientists from around the world. Nerve cells survived longer after injury in a group of mice that had high levels of NMNAT1, an indication that the normal form of the protein is protective, said Chen.

Prior to this, no one had seen an effect of a mutation of the protein in humans, he said.

"We can now identify the gene responsible for LCA in 75 percent of children," said first author of the study, Dr. Robert Koenekoop from the Research Institute of the McGill University Health Centre at The Montreal Children's Hospital and Associate Professor in Human Genetics and Ophthalmology in the Faculty of Medicine at McGill University. "We are getting closer to being able to identify all the genes for this form of child blindness and develop effective treatments."

In this study, he and his colleagues screened people with this disorder for the 16 genes known to be associated with the disease. There is no known cause for an estimated 30 percent of cases of the disease.

Chen and his colleagues then screened the exomes or protein-coding regions of the genomes of 50 individuals with the disease who did not have one of the known genetic mutations. They identified three who had NMNAT1 defects.

"That made this a good candidate gene," said Chen. "When we screened specifically for mutations in this gene in more patients, we found another four with this gene mutation. That confirmed our findings. Mutation in this gene caused the disease."

When the effect of NMNAT1 is totally lacking in mice, they die before birth, indicating the protein plays a crucial role in survival, said Chen.

"We speculate that in humans, this is a partial loss of function. In other words, the protein's activity is compromised, causing the problem in the eye. What we don't know is if it will have an effect later on in other organs.

"That's what makes this gene interesting. It is a brand new pathway for this disease, but its mode of molecular action is unclear," he said.

He said that children with the inherited eye disease not only have defects in their retinas (the light-sensing area of the eye) but they also have macular colobomas, which first appears around age 2 and progresses with age.

Others who took part in this work include Hui Wang, Xia Wang, Yiyun Chen, Yumei Li, Naimesh Solanki, Graeme Mardon, Huidan Xu, Jingliang Cheng, all of BCM; Qing Fu, Robert K Koenekoop, Jacek Majewski, Irma Lopez, Jeremy Schwartzentruber, Huanan Ren, Vafa Keser and Mohammed Nageeb, all of McGill University Health Centre in Montreal, Quebec, Canada; Chris F. Inglehearn, Bruce Hayward, David A. Parry, Carmel Toomes, Colin A Johnson, James A Poulter and Graham R Taylor of the University of Leeds in Leeds, UK; Gerald A Fishman and Mohammed Genead of Chicago Lighthouse for People who are Blind or Visually Impaired; Elias I. Traboulsi of the Cole Eye Institute in Cleveland, Ohio; Martin McKibbin of St. James University Hospital in Leeds, UK; Moin D. Mohamed, St. Thomas' Hospital in London, UK; Hussain Jafi of Gene-Tech Laboratories in Lahore, Pakistan; Yasmin Rashid of King Edward Medical University in Lahore, Pakistan and the Finding of Rare Disease Genes (FORGE) Canada Consortium.

First authors Koenekoop of McGill and Hui Wang of BCM contributed equally to the work.

Funding for this work came from the Foundation Fighting Blindness Canada, the Canadian Institutes for Health Research, the National Institutes of Health, Reseau Vision, the Fonds de la Recherche en Santé du Québec (FRSQ) and FORGE Canada, the Pangere Corporation, Grousbeck Foundation and the Wynn-Gund Foundation, for financial support. Also acknowledged are The Royal Society, Yorkshire Eye Research, The Sir Jules Thorn Charitable Trust, BCM­ Functional Genome Initiative (BCM-FGI) core facility supported by NIH shared instrument grant 1S10RR026550, the Graduate Innovation Foundation of Hunan Province, the Retina Research Foundation, the U.S. National Eye Institute, Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute (OGI-049), Genome Quebec and Genome British Columbia.