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WDR34 mutation from anencephaly patients impaired both SHH and PCP signaling pathways

Journal of Human Genetics volume 65, pages 985–993 (2020)Cite this article

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Abstract

Neural tube defects (NTDs) are debilitating human congenital abnormalities due to failure of neural tube closure. Sonic Hedgehog (SHH) signaling is required for dorsal–ventral patterning of the neural tube. The loss of activation in SHH signaling normally causes holoprosencephaly while the loss of inhibition causes exencephaly due to failure in neural tube closure. WDR34 is a dynein intermedia chain component which is required for SHH activation. However, Wdr34 knockout mouse exhibit exencephaly. Here we screened mutations in WDR34 gene in 100 anencephaly patients of Chinese Han population. Compared to 1000 Genome Project data, two potentially disease causing missense mutations of WDR34 gene (c.1177G>A; p.G393S and c.1310A>G; p.Y437C) were identified in anencephaly patients. These two mutations did not affect the protein expression level of WDR34. Luciferase reporter and endogenous target gene expression level showed that both mutations are lose-of-function mutations in SHH signaling. Surprisingly, WDR34 could promote planar cell polarity (PCP) signaling and the G393S lost this promoting effect on PCP signaling. Morpholino knockdown of wdr34 in zebrafish caused severe convergent extension defects and pericardial abnormalities. The G393S mutant has less rescuing effects than both WT and Y437C WDR34 in zebrafish. Our results suggested that mutation in WDR34 could contribute to human NTDs by affecting both SHH and PCP signaling.

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References

  1. Blencowe H, Kancherla V, Moorthie S, Darlison MW, Modell B. Estimates of global and regional prevalence of neural tube defects for 2015: a systematic analysis. Ann N Y Acad Sci. 2018;1414:31–46.

    PubMed  Google Scholar 

  2. Mitchell LE. Epidemiology of neural tube defects. Am J Med Genet C Semin Med Genet. 2005;135C:88–94.

    PubMed  Google Scholar 

  3. Botto LD, Moore CA, Khoury MJ, Erickson JD. Neural-tube defects. N Engl J Med. 1999;341:1509–19.

    CAS  PubMed  Google Scholar 

  4. Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, et al. Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res Part A Clin Mol Teratol. 2006;76:237–40.

    CAS  PubMed  Google Scholar 

  5. Li Y, Lu W, He X, Bu G. Modulation of LRP6-mediated Wnt signaling by molecular chaperone Mesd. FEBS Lett. 2006;580:5423–8.

    CAS  PubMed  Google Scholar 

  6. Wallingford JB, Niswander LA, Shaw GM, Finnell RH. The continuing challenge of understanding, preventing, and treating neural tube defects. Science.2013;339:1222002.

    PubMed  PubMed Central  Google Scholar 

  7. Leck I. Causation of neural tube defects: clues from epidemiology. Br Med Bull. 1974;30:158–63.

    CAS  PubMed  Google Scholar 

  8. Goetz SC, Anderson KV. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet. 2010;11:331–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Anvarian Z, Mykytyn K, Mukhopadhyay S, Pedersen LB, Christensen ST. Cellular signalling by primary cilia in development, organ function and disease. Nat Rev Nephrol. 2019;15:199–219.

    PubMed  PubMed Central  Google Scholar 

  10. He M, Agbu S, Anderson KV. Microtubule motors drive hedgehog signaling in primary cilia. Trends Cell Biol. 2017;27:110–25.

    CAS  PubMed  Google Scholar 

  11. Roberts AJ. Emerging mechanisms of dynein transport in the cytoplasm versus the cilium. Biochem Soc Trans. 2018;46:967–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hildebrandt F, Benzing T, Katsanis N. Ciliopathies. N Engl J Med. 2011;364:1533–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Reiter JF, Leroux MR. Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol. 2017;18:533–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Asante D, Stevenson NL, Stephens DJ. Subunit composition of the human cytoplasmic dynein-2 complex. J Cell Sci. 2014;127:4774–87.

    PubMed  PubMed Central  Google Scholar 

  15. Tsurumi Y, Hamada Y, Katoh Y, Nakayama K. Interactions of the dynein-2 intermediate chain WDR34 with the light chains are required for ciliary retrograde protein trafficking. Mol Biol Cell. 2019;30:658–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Huber C, Wu S, Kim AS, Sigaudy S, Sarukhanov A, Serre V, et al. WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-kappaB pathway in cilia. Am J Hum Genet. 2013;93:926–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Schmidts M, Vodopiutz J, Christou-Savina S, Cortes CR, McInerney-Leo AM, Emes RD, et al. Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy. Am J Hum Genet. 2013;93:932–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ruiz i Altaba A, Nguyen V, Palma V. The emergent design of the neural tube: prepattern, SHH morphogen and GLI code. Curr Opin Genet Dev. 2003;13:513–21.

    CAS  PubMed  Google Scholar 

  19. Patten I, Placzek M. The role of Sonic hedgehog in neural tube patterning. Cell Mol Life Sci. 2000;57:1695–708.

    CAS  PubMed  Google Scholar 

  20. Wilson L, Maden M. The mechanisms of dorsoventral patterning in the vertebrate neural tube. Dev Biol. 2005;282:1–13.

    CAS  PubMed  Google Scholar 

  21. Murdoch JN, Copp AJ. The relationship between sonic Hedgehog signaling, cilia, and neural tube defects. Birth Defects Res Part A Clin Mol Teratol. 2010;88:633–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Svard J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergstrom A, et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell. 2006;10:187–97.

    PubMed  Google Scholar 

  23. Maekawa M, Ohta K, Katagiri R, Ueta E, Naruse I. Exencephaly induction by valproic acid in the genetic polydactyly/arhinencephaly mouse, Pdn/Pdn. Congenit Anom. 2005;45:132–6.

    CAS  Google Scholar 

  24. Naruse I, Ueta E. Hydrocephalus manifestation in the genetic polydactyly/arhinencephaly mouse (Pdn/Pdn). Congenit Anom. 2002;42:27–31.

    Google Scholar 

  25. Wu C, Li J, Peterson A, Tao K, Wang B. Loss of dynein-2 intermediate chain Wdr34 results in defects in retrograde ciliary protein trafficking and Hedgehog signaling in the mouse. Hum Mol Genet. 2017;26:2386–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen Z, Lei Y, Zheng Y, Aguiar-Pulido V, Ross ME, Peng R, et al. Threshold for neural tube defect risk by accumulated singleton loss-of-function variants. Cell Res. 2018;28:1039–41.

    PubMed  PubMed Central  Google Scholar 

  27. Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68–74.

    Google Scholar 

  28. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40:W452–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–81.

    CAS  PubMed  Google Scholar 

  32. Krock BL, Mills-Henry I, Perkins BD. Retrograde intraflagellar transport by cytoplasmic dynein-2 is required for outer segment extension in vertebrate photoreceptors but not arrestin translocation. Investig Ophthalmol Vis Sci. 2009;50:5463–71.

    Google Scholar 

  33. Ybot-Gonzalez P, Savery D, Gerrelli D, Signore M, Mitchell CE, Faux CH, et al. Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure. Development. 2007;134:789–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Copp AJ, Greene ND. Neural tube defects-disorders of neurulation and related embryonic processes. Wiley Interdiscip Rev Dev Biol. 2013;2:213–27.

    CAS  PubMed  Google Scholar 

  35. Kibar Z, Torban E, McDearmid JR, Reynolds A, Berghout J, Mathieu M, et al. Mutations in VANGL1 associated with neural-tube defects. N Engl J Med. 2007;356:1432–7.

    CAS  PubMed  Google Scholar 

  36. Lei YP, Zhang T, Li H, Wu BL, Jin L, Wang HY. VANGL2 mutations in human cranial neural-tube defects. N Engl J Med. 2010;362:2232–5.

    CAS  PubMed  Google Scholar 

  37. Juriloff DM, Harris MJ. A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects. Birth Defects Res Part A Clin Mol Teratol. 2012;94:824–40.

    CAS  PubMed  Google Scholar 

  38. Copp AJ, Stanier P, Greene ND. Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurol. 2013;12:799–810.

    PubMed  PubMed Central  Google Scholar 

  39. Araya C, Ward LC, Girdler GC, Miranda M. Coordinating cell and tissue behavior during zebrafish neural tube morphogenesis. Dev Dyn. 2016;245:197–208.

    PubMed  Google Scholar 

  40. Cearns MD, Escuin S, Alexandre P, Greene ND, Copp AJ. Microtubules, polarity and vertebrate neural tube morphogenesis. J Anat. 2016;229:63–74.

    PubMed  PubMed Central  Google Scholar 

  41. Jussila M, Ciruna B. Zebrafish models of non-canonical Wnt/planar cell polarity signalling: fishing for valuable insight into vertebrate polarized cell behavior. Wiley Interdiscip Rev Dev Biol. 2017;6:3.

    Google Scholar 

  42. Toropova K, Zalyte R, Mukhopadhyay AG, Mladenov M, Carter AP, Roberts AJ. Structure of the dynein-2 complex and its assembly with intraflagellar transport trains. Nat Struct Mol Biol. 2019;26:823–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Luo X, Liu Y, Ma S, Liu L, Xie R, Wang S. WDR34 activates Wnt/Beta-catenin signaling in hepatocellular carcinoma. Dig Dis Sci. 2019;64:2591–9.

    CAS  PubMed  Google Scholar 

  44. Yan D, Wallingford JB, Sun TQ, Nelson AM, Sakanaka C, Reinhard C, et al. Cell autonomous regulation of multiple Dishevelled-dependent pathways by mammalian Nkd. Proc Natl Acad Sci USA. 2001;98:3802–7.

    CAS  PubMed  Google Scholar 

  45. De Marco P, Merello E, Consales A, Piatelli G, Cama A, Kibar Z, et al. Genetic analysis of disheveled 2 and disheveled 3 in human neural tube defects. J Mol Neurosci. 2013;49:582–8.

    CAS  PubMed  Google Scholar 

  46. Li Y, Klena NT, Gabriel GC, Liu X, Kim AJ, Lemke K, et al. Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature. 2015;521:520–4.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants to YZ from the National Natural Science Foundation of China (81870894, 81741048), the National Key Research and Development Program (2018YFA0800303); and Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-07-E00041).

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Authors and Affiliations

  1. Obstetrics & Gynecology Hospital, Institute of Reproduction & Development, Fudan University, Shanghai, China

    Hailing Yin, Rui Peng, Zhongzhong Chen, Hongyan Wang & Yufang Zheng

  2. Institute of Developmental Biology & Molecular Medicine, Fudan University, Shanghai, China

    Hailing Yin & Yufang Zheng

  3. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China

    Hongyan Wang & Yufang Zheng

  4. Capital Institute of Pediatrics, Beijing, China

    Ting Zhang

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  1. Hailing Yin
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YZ designed the study and wrote the paper. HY performed the Sanger sequencing, luciferase, and zebrafish experiments, RP and ZC performed sequence analysis. TZ and HW recruited the patients. All authors reviewed the paper and contributed to scientific content.

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Correspondence to Yufang Zheng.

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Yin, H., Peng, R., Chen, Z. et al. WDR34 mutation from anencephaly patients impaired both SHH and PCP signaling pathways. J Hum Genet 65, 985–993 (2020). https://doi.org/10.1038/s10038-020-0793-z

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