Whole DNA sequencing reveals mutations, new gene for blinding disease

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.

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

New PRA gene identified in Phalenes and Papillons

Aug 29, 2013

Finnish researchers have identified a genetic mutation causing progressive retinal atrophy (PRA) in the Phalene and Papillon dog breeds. PRA is one of the most common causes of blindness in dogs and in human. ...

Moving towards gene therapies for retinal atrophies

Sep 09, 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

Jun 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 techno ...

Researchers find new genetic cause of blinding eye disease

Aug 09, 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 ...

Recommended for you

Right environment could improve stem cell therapies

Oct 23, 2014

Stem cell therapies are being hailed as a potential cure for many major health conditions, but there is much still to learn about the highly complex environments needed to optimise these therapies, according to researchers ...

User comments