期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 40, 页码 16139-16144出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1308243110
关键词
medical genetics; ophthalmology; ciliopathy; retinal blindness
资金
- Swiss National Science Foundation [310030_138346]
- Gebert Ruf Foundation, Switzerland
- Foundation Fighting Blindness
- National Institutes of Health [DK072301, MH-084018]
- Ministry of Health, Labor and Welfare (MHLW) of Japan [23300101, 23300201]
- MHLW
- Japan Science and Technology Agency
- Strategic Research Program for Brain Sciences
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [23592603, 24118001, 24118007, 23300101] Funding Source: KAKEN
- Swiss National Science Foundation (SNF) [310030_138346] Funding Source: Swiss National Science Foundation (SNF)
We 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. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we 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. We detected homozygous or compound heterozygous mutations 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 similar to 446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we 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 NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our 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.
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