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Human Genetics

, Volume 135, Issue 12, pp 1375–1387 | Cite as

A mutation in ADIPOR1 causes nonsyndromic autosomal dominant retinitis pigmentosa

  • Jinlu Zhang
  • Changguan Wang
  • Yan Shen
  • Ningning Chen
  • Likun Wang
  • Ling Liang
  • Tong Guo
  • Xiaobei Yin
  • Zhizhong Ma
  • Bo ZhangEmail author
  • Liping YangEmail author
Original Investigation

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.

Keywords

Retinitis Pigmentosa Zebrafish Embryo Retinal Pigment Epithelium Unaffected Family Member Retinitis Pigmentosa Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants

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.

Informed consent

Informed consent was obtained from all individual participants or guardians on behalf of all of the minors/children participants included in the study.

Research involving animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

439_2016_1730_MOESM1_ESM.tif (7.3 mb)
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)
439_2016_1730_MOESM2_ESM.docx (13 kb)
Supplementary material 2 (DOCX 13 kb)
439_2016_1730_MOESM3_ESM.docx (14 kb)
Supplementary material 3 (DOCX 13 kb)

References

  1. Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. doi: 10.1002/0471142905.hg0720s76 PubMedPubMedCentralGoogle Scholar
  2. Bazan NG (2006) Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci 29:263–271CrossRefPubMedGoogle Scholar
  3. Bazan NG (2007) Homeostatic regulation of photoreceptor cell integrity: significance of the potent mediator neuroprotectin D1 biosynthesized from docosahexaenoic acid: the Proctor Lecture. Invest Ophthalmol Vis Sci 48:4866–4881CrossRefPubMedGoogle Scholar
  4. Bazan NG, Molina MF, Gordon WC (2011) Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer’s, and other neurodegenerative diseases. Annu Rev Nutr 31:321–351CrossRefPubMedPubMedCentralGoogle Scholar
  5. Berg AH, Combs TP, Scherer PE (2002) ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 13:84–89CrossRefPubMedGoogle Scholar
  6. Chizzolini M, Galan A, Milan E, Sebastiani A, Costagliola C, Parmeggiani F (2011) Good epidemiologic practice in retinitis pigmentosa: from phenotyping to biobanking. Curr Genomics 12:260–266CrossRefPubMedPubMedCentralGoogle Scholar
  7. Fu Q, Wang F, Wang H et al (2013) Nest-generation sequencing-based molecular diagnosis of a Chinese patient cohort with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci 54:4158–4166CrossRefPubMedPubMedCentralGoogle Scholar
  8. Fu Z, Lofqvist CA, Shao Z et al (2015) Dietary ω-3 polyunsaturated fatty acids decrease retinal neovascularization by adipose-endoplasmic reticulum stress reduction to increase adiponectin. Am J Clin Nutr 101:879–888CrossRefPubMedPubMedCentralGoogle Scholar
  9. Fu Z, Gong Y, Löfqvist C, Hellström A, Smith LE (2016) Review: adiponectin in retinopathy. Biochim Biophys Acta 1862:1392–1400CrossRefPubMedGoogle Scholar
  10. Higuchi A, Ohashi K, Kihara S, Walsh K, Ouchi N (2009) Adiponectin suppresses pathological microvessel formation in retina through modulation of tumor necrosis factor-alpha expression. Circ Res 104:1058–1065CrossRefPubMedPubMedCentralGoogle Scholar
  11. Holland WL, Miller RA, Wang ZV et al (2011) Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17:55–63CrossRefPubMedGoogle Scholar
  12. Hsieh MH, Goodman HM (2005) A novel gene family in Arabidopsis encoding putative heptahelical transmembrane proteins homologous to human adiponectin receptors and progestin receptors. J Exp Bot 56:3137–3147CrossRefPubMedGoogle Scholar
  13. Iwabu M, Yamauchi T, Okada-Iwabu M et al (2010) Adiponectin and AdipoR1 regulate PGC-1-alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 464:1313–1319CrossRefPubMedGoogle Scholar
  14. Kaarniranta K, Paananen J, Nevalainen T et al (2012) Adiponection receptor 1 gene (ADIPOR1) variant is associated with advanced age-related macular degeneration in Finnish population. Neurosci Lett 513:233–237CrossRefPubMedGoogle Scholar
  15. Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451CrossRefPubMedGoogle Scholar
  16. Krumm N, Sudmant PH, Ko A et al (2012) Copy number variation detection and genotyping from exome sequence data. Genome Res 22:1525–1532CrossRefPubMedPubMedCentralGoogle Scholar
  17. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760CrossRefPubMedPubMedCentralGoogle Scholar
  18. Li H, Handsaker B, Wysoker A et al (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25:2078–2079CrossRefPubMedPubMedCentralGoogle Scholar
  19. Lin T, Qiu Y, Liu Y, Mohan R, Li Q, Lei B (2013) Expression of adiponectin and its receptors in type 1 diabetes mellitus in human and mouse retinas. Mol Vis 19:1769–1778PubMedPubMedCentralGoogle Scholar
  20. Lyzogubov VV, Tytarenko RG, Bora NS, Bora PS (2012) Inhibitory role of adiponectin peptide I on rat choroidal neovascularization. Biochim Biophys Acta 1823:1264–1272CrossRefPubMedGoogle Scholar
  21. Mao D, Peng H, Li Q et al (2012) Aqueous humor and plasma adiponectin levels in proliferative diabetic retinopathy patients. Curr Eye Res 37:803–808CrossRefPubMedGoogle Scholar
  22. Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814CrossRefPubMedPubMedCentralGoogle Scholar
  23. Nishiguchi KM, Tearle RG, Liu YP et al (2013) Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene. Proc Natl Acad Sci USA 110:16139–16144CrossRefPubMedPubMedCentralGoogle Scholar
  24. Nishio S, Gibert Y, Bernard L, Brunet F, Triqueneaux G, Laudet V (2008) Adiponectin and adiponectin receptor genes are coexpressed during zebrafish embryogenesis and regulated by food deprivation. Dev Dyn 237:1682–1690CrossRefPubMedGoogle Scholar
  25. Omae T, Nagaoka T, Yoshida A (2015) Relationship between retinal blood flow and serum Adiponectin concentrations in patients with Type 2 diabetes mellitus. Invest Ophthalmol Vis Sci 56:4143–4149CrossRefPubMedGoogle Scholar
  26. Rice DS, Calandria JM, Gordon WC et al (2015) Adiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cellsurvival. Nat Commun 6:6228CrossRefPubMedPubMedCentralGoogle Scholar
  27. Schwarz JM, Rödelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7:575–576CrossRefPubMedGoogle Scholar
  28. Tanabe H, Fujii Y, Okada-Iwabu M et al (2015) Crystal structures of the human adiponectin receptors. Nature 520:312–316CrossRefPubMedPubMedCentralGoogle Scholar
  29. Tang YT, Hu T, Arterburn M, Boyle B, Bright JM, Emtage PC, Funk WD (2005) PAQR proteins: a novel membrane receptor family defined by an ancient 7-transmembrane pass motif. J Mol Evol 61:372–380CrossRefPubMedGoogle Scholar
  30. Wang F, Li H, Xu M et al (2014) A homozygous missense mutation in NEUROD1 is associated with nonsyndromic autosomal recessive retinitispigmentosa. Invest Ophthalmol Vis Sci 56:150–155CrossRefPubMedGoogle Scholar
  31. Worth CL, Preissner R, Blundell TL (2011) SDM–a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res 39:W215–W222CrossRefPubMedPubMedCentralGoogle Scholar
  32. Wright AF, Chakarova CF, Abd El-Aziz MM, Bhattacharya SS (2010) Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet 11:273–284CrossRefPubMedGoogle Scholar
  33. Xu L, Hu L, Ma K, Li J, Jonas JB (2006) Prevalence of retinitis pigmentosa in urban and rural adult Chinese: the Beijing Eye Study. Eur J Ophthalmol 16:865–866PubMedGoogle Scholar
  34. Xu M, Eblimit A, Wang J et al (2016) ADIPOR1 is mutated in syndromic retinitis pigmentosa. Hum Mutat 37:246–249CrossRefPubMedGoogle Scholar
  35. Yamauchi T, Kadowaki T (2013) Adiponectin receptor as a key player in healthy longevity and obesity-related diseases. Cell Metab 17:185–196CrossRefPubMedGoogle Scholar
  36. Yamauchi T, Nio Y, Maki T et al (2007) Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13:332–339CrossRefPubMedGoogle Scholar
  37. Yang L, Cui H, Yin X et al (2015) Dependable and efficient clinical molecular diagnosis of Chinese RP patient with targeted Exon sequencing. PLoS One 10:e0140684CrossRefPubMedPubMedCentralGoogle Scholar
  38. Zhao L, Wang F, Wang H et al (2015) Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland. Hum Genet 134:217–230CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Key Laboratory of Vision Loss and Restoration, Department of Ophthalmology, Ministry of EducationPeking University Third HospitalBeijingPeople’s Republic of China
  2. 2.Key Laboratory of Cell Proliferation and Differentiation of Ministry of Education, School of Life SciencesPeking UniversityBeijingPeople’s Republic of China
  3. 3.Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, Institute of Systems Biomedicine, School of Basic Medical SciencesPeking University Health Science CenterBeijingPeople’s Republic of China
  4. 4.Department of Ophthalmologythe Affiliated Hospital of Qingdao UniversityQingdaoPeople’s Republic of China

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