Abstract
Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness, visual field constriction, and severely reduced visual acuity. Despite a number of genes being implicated in RP pathogenesis, the genetic etiology of the disease remains unknown in many patients. In this study, our aim was to identify the disease-causing mutation of a large Chinese family with autosomal dominant RP (adRP). Targeted exon capture sequencing was initially performed to screen mutations in known disease-causing genes, followed by exome sequencing. In doing so, a heterozygous mutation in ADIPOR1 (c.929A > G) that results in an amino acid substitution (p.Y310C) was identified to co-segregate with the disease phenotype in this family. Adipor1 is wildly expressed throughout the body, but appears to be enriched in the photoreceptor inner and outer segments. The p.Y310C mutation, predicted to affect the structure and function of the protein, was confirmed to affect protein folding and its subcellular localization in vitro. In addition, knockdown of adipor1 expression in a zebrafish model with morpholino (MO) preferentially reduced the number of rod photoreceptors, with no effect on the number of cones, a phenotype that is characteristic of RP. Furthermore, the knockdown phenotype was partially rescued by injecting wild-type, but not mutant, human ADIPOR1 mRNA. We conclude that ADIPOR1 is a novel adRP-causing gene and plays an important role in rod development and maintenance.
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Acknowledgments
The authors thank the patients and their family members for their participation in this study. This study was supported by the National Natural Science Foundation of China (http://www.nsfc.gov.cn/ Grant Numbers: 81170877, 81470666 LY and 81371264 BZ); the clinical Key Project of Peking University Third Hospital (BYSY2014004 LY); the Seeding Grant for Medicine and Life Sciences of Peking University (2014-MB-20 LY); 973 program (2015CB942803), a Peking University grant for translational research (ZM and BZ).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Peking University Third Hospital Medical Ethics Committee (No. 2012093) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants or guardians on behalf of all of the minors/children participants included in the study.
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J. Zhang, C. Wang, and Y. Shen are co-first authors.
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Fig. S1
Screenshot of the SDM analysis results for the Y310C mutation in ADIPOR1. On the left, information about the wildtype and mutant residue is displayed as well as the predicted effect on protein stability. In the middle, the structural context of the wildtype and mutant amino acids are shown in the Jmol applet with the residues colored blue (Y) and yellow (C), respectively (TIFF 7478 kb)
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Zhang, J., Wang, C., Shen, Y. et al. A mutation in ADIPOR1 causes nonsyndromic autosomal dominant retinitis pigmentosa. Hum Genet 135, 1375–1387 (2016). https://doi.org/10.1007/s00439-016-1730-2
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DOI: https://doi.org/10.1007/s00439-016-1730-2