Whole DNA sequencing reveals mutations, new gene for blinding disease

September 16, 2013

Retinitis pigmentosa (RP) is a genetic disease that causes progressive loss of vision and is caused by mutations in more than 50 genes. Conventional methods for identification of both RP mutations and novel RP genes involve the screening of DNA coding sequences.

In a paper in the Proceedings of the National Academy of Sciences, researchers from the Massachusetts Eye and Ear, Harvard Medical School, the University of Lausanne, Switzerland, and others tested DNA with the use of , a technique that takes into account all variants from both the coding and noncoding regions of the . With this approach the authors report a number of unique RP mutations, a previously undescribed called NEK2 that involves the retinal photoreceptors, and structural DNA rearrangements originating in introns.

This paper supports the advantages of the use of whole to search for mutations in patients with RP.

The researchers performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants, the authors wrote. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers.

Using a specific work flow, they assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. They detected homozygous or compound het erozygous in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of 446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing.

Moreover, in another Japanese patient, they identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonine-protein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2mRNA.

In addition to identifying a previously undescribed ARRP gene, the study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome.

Explore further: Mutations in a gene that impacts immune function increase susceptibility to prostate cancer

More information: Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene, www.pnas.org/cgi/doi/10.1073/pnas.1308243110

Related Stories

Mutations in a gene that impacts immune function increase susceptibility to prostate cancer

August 29, 2013
A team of researchers led by Janet Stanford, Ph.D., of Fred Hutchinson Cancer Research Center has discovered that mutations in the gene BTNL2, which encodes a protein involved in regulating T-cell proliferation and cytokine ...

Moving towards gene therapies for retinal atrophies

September 9, 2013
Researchers at Michigan State University (MSU) provide the first phenotypic evidence a mutated gene causes one form of progressive retinal atrophy in papillon dogs. Progressive retinal atrophy is analogous to one of the leading ...

Whole genome or exome sequencing: An individual insight

June 27, 2013
Focusing on parts rather than the whole, when it comes to genome sequencing, might be extremely useful, finds research in BioMed Central's open access journal Genome Medicine. The research compares several sequencing technologies ...

Researchers find new genetic cause of blinding eye disease

August 9, 2011
Combining the expertise of several different labs, University of Iowa researchers have found a new genetic cause of the blinding eye disease retinitis pigmentosa (RP) and, in the process, discovered an entirely new version ...

Goal of identifying nearly all genetic causes of deafness is within reach

June 20, 2013
At least half of all cases of deafness that develop from birth through infancy in developed countries have a genetic basis, as do many cases of later onset progressive hearing loss. To date, at least 1,000 mutations occurring ...

Recommended for you

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 ...

Newly discovered gene variants link innate immunity and Alzheimer's disease

July 17, 2017
Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, ...

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.