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Two novel CHN1 variants identified in Duane retraction syndrome pedigrees disrupt development of ocular motor nerves in zebrafish

Journal of Human Genetics volume 69, pages 33–39 (2024)Cite this article

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Abstract

Duane retraction syndrome (DRS) is a rare congenital eye movement disorder causing by the dysplasia of abducens nerve, and has highly variable phenotype. MRI can reveal the endophenotype of DRS. Most DRS cases are sporadical and isolated, while some are familial or accompanied by other ocular disorders and systemic congenital abnormalities. CHN1 was the most common causative gene for familial DRS. Until now, 13 missense variants of CHN1 have been reported. In this study, we enrolled two unrelated pedigrees with DRS. Detailed clinical examinations, MRI, and the whole exome sequencing (WES) were performed to reveal their clinical and genetic characteristics. Patients from pedigree-1 presented with isolated DRS, and a novel heterozygous variant c.650 A > G, p. His217Arg was identified in CHN1 gene. Patients from pedigree-2 presented with classic DRS and abnormalities in auricle morphology, and the pedigree segregated another novel heterozygous CHN1 variant c.637 T > C, p. Phe213Leu. A variety of bioinformatics software predicted that the two variants had deleterious or disease-causing effects. After injecting of two mutant CHN1 mRNAs into zebrafish embryos, the dysplasia of ocular motor nerves (OMN) was observed. Our present findings expanded the phenotypic and genotypic spectrum of CHN1 related DRS, as well as provided new insights into the role of CHN1 in OMN development. Genetic testing is strongly recommended for patients with a DRS family history or accompanying systemic congenital abnormalities.

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References

  1. Gaur N, Sharma P. Management of Duane retraction syndrome: A simplified approach. Indian J Ophthalmol. 2019;67:16–22.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Miller NR, Kiel SM, Green WR, Clark AW. Unilateral Duane’s retraction syndrome (Type 1). Arch Ophthalmol. 1982;100:1468–72.

    Article  CAS  PubMed  Google Scholar 

  3. Demer JL, Clark RA, Lim KH, Engle EC. Magnetic resonance imaging evidence for widespread orbital dysinnervation in dominant Duane’s retraction syndrome linked to the DURS2 locus. Investig Ophthalmol Vis Sci. 2007;48:194–202.

    Article  Google Scholar 

  4. Suma U, Ferzana M, Babitha V, Jyothi P. Clinical profile and magnetic resonance imaging characteristics of Duane retraction syndrome. Oman J Ophthalmol. 2022;15:147–52.

    PubMed  PubMed Central  Google Scholar 

  5. Whitman MC, Engle EC. Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance. Hum Mol Genet. 2017;26:R37–R44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Masoomian B, Akbari MR, Mirmohamadsadeghi A, Aghsaei Fard M, Khorrami-Nejad M, Hamad N, et al. Clinical characteristics and surgical approach in Duane retraction syndrome: a study of 691 patients. Jpn J Ophthalmol. 2022;66:474–80.

    Article  PubMed  Google Scholar 

  7. Chen X, Fu Z, Yu J, Ding H, Bai J, Chen J, et al. Prevalence of amblyopia and strabismus in Eastern China: results from screening of preschool children aged 36-72 months. Br J Ophthalmol. 2016;100:515–9.

    Article  PubMed  Google Scholar 

  8. Kocamaz M, Aygit ED, Inal A, Ocak OB, Cicek U, Gokyigit B. Duane Retraction Syndrome and Accompanying Ocular Abnormalities. Beyoglu Eye J. 2019;4:28–31.

    PubMed  PubMed Central  Google Scholar 

  9. Donovan KA, An J, Nowak RP, Yuan JC, Fink EC, Berry BC, et al. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife. 2018;7:e38430.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Jia H, Ma Q, Liang Y, Wang D, Chang Q, Zhao B, et al. Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders. Orphanet J Rare Dis. 2022;17:431.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kekunnaya R, Negalur M. Duane retraction syndrome: causes, effects and management strategies. Clin Ophthalmol. 2017;11:1917–30.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Oystreck DT, Engle EC, Bosley TM. Recent progress in understanding congenital cranial dysinnervation disorders. J Neuroophthalmol. 2011;31:69–77.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Godfrey D, Torres A, Heidary G, Zahoor H, Lee A, Berry G, et al. A 7-year-old female with arthrogryposis multiplex congenita, Duane retraction syndrome, and Marcus Gunn phenomenon due to a ZC4H2 gene mutation: a clinical presentation of the Wieacker-Wolff syndrome. Ophthalmic Genet. 2021;42:612–4.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Pascolini G, Passarelli C, Lipari M, Chandramouli B, Chillemi G, Di Giosaffatte N, et al. Duane retraction syndrome characterized by inner ear agenesis and neurodevelopmental phenotype in an Italian family with a variant in MAFB. Clin Genet. 2022;101:377–8.

    Article  CAS  PubMed  Google Scholar 

  15. Sato Y, Tsukaguchi H, Morita H, Higasa K, Tran MTN, Hamada M, et al. A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome. Kidney Int. 2018;94:396–407.

    Article  CAS  PubMed  Google Scholar 

  16. Bosley TM, Salih MA, Alorainy IA, Oystreck DT, Nester M, Abu-Amero KK, et al. Clinical characterization of the HOXA1 syndrome BSAS variant. Neurology. 2007;69:1245–53.

    Article  CAS  PubMed  Google Scholar 

  17. Ajam-Hosseini M, Parvini F, Angaji A. A novel de novo nonsense mutation in SALL4 causing duane radial ray syndrome: a case report and expanding the phenotypic spectrum. BMC Med Genom. 2023;16:33.

    Article  CAS  Google Scholar 

  18. Miyake N, Andrews C, Fan W, He W, Chan WM, Engle EC. CHN1 mutations are not a common cause of sporadic Duane’s retraction syndrome. Am J Med Genet A. 2010;152A:215–7.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Barry BJ, Whitman MC, Hunter DG, Engle EC. Duane Syndrome. 2007 May 25 [Updated 2019 Aug 29]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle. p. 1993–2023.

  20. Rose R, Golosova O, Sukhomlinov D, Tiunov A, Prosperi M. Flexible design of multiple metagenomics classification pipelines with UGENE. Bioinformatics. 2019;35:1963–5.

    Article  CAS  PubMed  Google Scholar 

  21. Chen CW, Lin MH, Liao CC, Chang HP, Chu YW. iStable 2.0: Predicting protein thermal stability changes by integrating various characteristic modules. Comput Struct Biotechnol J. 2020;18:622–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pan Q, Nguyen TB, Ascher DB, Pires DEV. Systematic evaluation of computational tools to predict the effects of mutations on protein stability in the absence of experimental structures. Brief Bioinform. 2022;23:bbac025.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Marabotti A, Del Prete E, Scafuri B, Facchiano A. Performance of Web tools for predicting changes in protein stability caused by mutations. BMC Bioinforma. 2021;22:345.

    Article  CAS  Google Scholar 

  24. Clark C, Austen O, Poparic I, Guthrie S. α2-Chimaerin regulates a key axon guidance transition during development of the oculomotor projection. J Neurosci. 2013;33:16540–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Carretero-Rodriguez L, Guðjónsdóttir R, Poparic I, Reilly ML, Chol M, Bianco IH, et al. The Rac-GAP alpha2-Chimaerin Signals via CRMP2 and Stathmins in the Development of the Ocular Motor System. J Neurosci. 2021;41:6652–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen HL, Yuh CH, Wu KK. Nestin is essential for zebrafish brain and eye development through control of progenitor cell apoptosis. PLoS ONE. 2010;5:e9318.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zannino DA, Appel B. Olig2+ precursors produce abducens motor neurons and oligodendrocytes in the zebrafish hindbrain. J Neurosci. 2009;29:2322–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Parsa CF, Robert MP. Thromboembolism and Congenital Malformations: From Duane Syndrome to Thalidomide Embryopathy. JAMA Ophthalmol. 2013;131:439–47.

    Article  CAS  PubMed  Google Scholar 

  29. Miyake N, Chilton J, Psatha M, Cheng L, Andrews C, Chan WM, et al. Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane’s retraction syndrome. Science. 2008;321:839–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Appukuttan B, Gillanders E, Juo SH, Freas-Lutz D, Ott S, Sood R, et al. Localization of a gene for Duane retraction syndrome to chromosome 2q31. Am J Hum Genet. 1999;65:1639–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhou TC, Duan WH, Fu XL, Zhu Q, Guo LY, Zhou Y, et al. Identification of a novel CHN1 p. (Phe213Val) variant in a large Han Chinese family with congenital Duane retraction syndrome. Sci Rep. 2020;10:16225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Miyake N, Demer JL, Shaaban S, Andrews C, Chan WM, Christiansen SP, et al. Expansion of the CHN1 strabismus phenotype. Investig Ophthalmol Vis Sci. 2011;52:6321–8.

    Article  CAS  Google Scholar 

  33. Chan WM, Miyake N, Zhu-Tam L, Andrews C, Engle EC. Two novel CHN1 mutations in 2 families with Duane retraction syndrome. Arch Ophthalmol. 2011;129:649–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Biler ED, Ilim O, Onay H, Uretmen O. CHN1 gene mutation analysis in patients with Duane retraction syndrome. J AAPOS. 2017;21:472–475.e2.

    Article  PubMed  Google Scholar 

  35. Angelini C, Trimouille A, Arveiler B, Espil-Taris C, Ichinose N, Lasseaux E, et al. CHN1 and duane retraction syndrome: Expanding the phenotype to cranial nerves development disease. Eur J Med Genet. 2021;64:104188.

    Article  CAS  PubMed  Google Scholar 

  36. Bosley TM, Alorainy IA, Salih MA, Aldhalaan HM, Abu-Amero KK, Oystreck DT, et al. The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet A. 2008;146A:1235–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Demer JL, Ortube MC, Engle EC, Thacker N. High-resolution magnetic resonance imaging demonstrates abnormalities of motor nerves and extraocular muscles in patients with neuropathic strabismus. J AAPOS. 2006;10:135–42.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Nugent AA, Park JG, Wei Y, Tenney AP, Gilette NM, DeLisle MM, et al. Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome. J Clin Investig. 2017;127:1664–82.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the family members for their participation in the study, and the Institute of Zoology, Chinese Academy of Sciences, for providing zebrafish experiment assistance. This work was supported by the National Natural Science Foundation of China (No.82070999), and the Natural Science Foundation of Beijing, China (No.7212017).

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Authors and Affiliations

  1. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, 100730, Beijing, China

    Ranran Zhang, Hongyan Jia, Chuzhi Peng, Qian Ma, Yi Liang & Yonghong Jiao

  2. Beijing Ophthalmology and Visual Science Key Lab, 100730, Beijing, China

    Ranran Zhang, Hongyan Jia, Chuzhi Peng, Qian Ma, Yi Liang & Yonghong Jiao

  3. Department of Radiology, Beijing Tongren Hospital, Capital Medical University, 100730, Beijing, China

    Qinglin Chang & Zongrui Zhang

  4. Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100020, Beijing, China

    Shuyan Yang

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Contributions

YJ and SY designed the project. RZ, HJ, QM, and YL provided the clinical data. QC and ZZ provided the MRI results. RZ, HJ and SY analyzed the genetic data. RZ, CP and SY completed the experiment. RZ and HJ wrote the manuscript. YJ and SY supervised the study and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Shuyan Yang or Yonghong Jiao.

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Zhang, R., Jia, H., Chang, Q. et al. Two novel CHN1 variants identified in Duane retraction syndrome pedigrees disrupt development of ocular motor nerves in zebrafish. J Hum Genet 69, 33–39 (2024). https://doi.org/10.1038/s10038-023-01201-w

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