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Expanding the phenotypic spectrum and clinical severity associated with WLS gene

Journal of Human Genetics volume 68, pages 607–613 (2023)Cite this article

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Abstract

WLS (Wnt ligand secretion mediator or Wntless) orchestrates the secretion of all Wnt proteins, a family of evolutionary conserved proteins, involved in Wnt signaling pathway that has many essential biological functions including the regulation of development, cell proliferation, migration and apoptosis. Biallelic variants in WLS have recently been described in 10 patients with pleiotropic multiple congenital anomalies (MCA) known as Zaki syndrome. We identified a likely disease-causing variant in WLS (c.1579G>A, p.Gly527Arg) in a boy presented with a broad range of MCA including microcephaly, facial dysmorphism, alopecia, ophthalmologic anomalies, and complete soft tissue syndactyly. These features were reminiscent of Zaki syndrome although variable clinical severity was observed. In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation. As such, we extend the phenotype linked to Zaki syndrome. This study further highlights the importance of a thorough clinical evaluation to delineate the phenotypic spectrum associated with WLS variants and suggests that genotype-phenotype correlations due to variant localization seems likely. However, future work on additional patients and more functional studies may give further insights into genotype-phenotype correlations and the complex function of WLS.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

References

  1. Das S, Yu S, Sakamori R, Stypulkowski E, Gao N. Wntless in Wnt secretion: molecular, cellular and genetic aspects. Front Biol (Beijing). 2012;7:587–93.

    Article  CAS  PubMed  Google Scholar 

  2. Bartscherer K, Pelte N, Ingelfinger D, Boutros M. Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell. 2006;125:523–33.

    Article  CAS  PubMed  Google Scholar 

  3. Banziger C, Soldini D, Schutt C, Zipperlen P, Hausmann G, Basler K. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 2006;125:509–22.

    Article  CAS  PubMed  Google Scholar 

  4. Nygaard R, Yu J, Kim J, Ross DR, Parisi G, Clarke OB, et al. Structural basis of WLS/Evi-mediated Wnt transport and secretion. Cell 2021;184:194.e14–206.e14.

    Article  Google Scholar 

  5. Yu J, Chia J, Canning CA, Jones CM, Bard FA, Virshup DM. WLS retrograde transport to the endoplasmic reticulum during Wnt secretion. Dev Cell. 2014;29:277–91.

    Article  CAS  PubMed  Google Scholar 

  6. Chai G, Szenker-Ravi E, Chung C, Li Z, Wang L, Khatoo M, et al. A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion. N Engl J Med. 2021;385:1292–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. van Amerongen R, Berns A. Knockout mouse models to studyWnt signal transduction. Trends Genet. 2006;22:678–89.

    Article  PubMed  Google Scholar 

  8. Ikeya M, Lee S, Johnson J, McMahon A, Takada S. Wntsignalling required for expansion of neural crest and CNS pro-genitors. Nature 1997;389:966–70.

    Article  CAS  PubMed  Google Scholar 

  9. Preising MN, Görg B, Friedburg C, Qvartskhava N, Budde BS, Bonus M, et al. Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration. FASEB J 2019;33:11507–27. https://doi.org/10.1096/fj.201900914RR.

    Article  CAS  PubMed  Google Scholar 

  10. McMahon AP, Bradley A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 1990;62:1073–85.

    Article  CAS  PubMed  Google Scholar 

  11. Rowitch DH, Danielian PS, McMahon AP, Zec N. Cystic malformation of the posterior cerebellar vermis transgenic mice that ectopically express engrailed-1, a homeodomain transcription factor. Teratology 1990;60:22–8.

    Article  Google Scholar 

  12. Cavodeassi F, Carreira-Barbosa F, Young RM, Concha ML, Allende ML, Houart C, et al. Early stages of zebrafish eye formation require the coordinated activity of Wnt11, Fz5, and the Wnt/beta-catenin pathway. Neuron 2005;47:43–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu C, Bakeri H, Li T, Swaroop A. Regulation of retinal progenitor expansion by Frizzled receptors: implications for microphthalmia and retinal coloboma. Hum Mol Genet. 2012;21:1848–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu C, Widen SA, Williamson KA, Ratnapriya R, Gerth-Kahlert C, Rainger J, et al. A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma. Hum Mol Genet. 2016;25:1382–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hagglund AC, Berghard A, Carlsson L. Canonical Wnt/beta-catenin signalling is essential for optic cup formation. PLoS ONE. 2013;8:e81158.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lieven O, Ruther U. The Dkk1 dose is critical for eye development. Dev Biol. 2011;355:124–37.

    Article  CAS  PubMed  Google Scholar 

  17. Veien ES, Rosenthal JS, Kruse-Bend RC, Chien CB, Dorsky RI. Canonical Wnt signaling is required for the maintenance of dorsal retinal identity. Development. 2008;135:4101–11.

    Article  CAS  PubMed  Google Scholar 

  18. Joeng KS, Lee YC, Jiang MM, Bertin TK, Chen Y, Abraham AM, et al. The swaying mouse as a model of osteogenesis imperfect caused by WNT1 mutations. Hum Mol Genet. 2014;23:4035–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, et al. Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet. 2013;92:565–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tamura M, Nemoto E. Role of the Wnt signaling molecules in the tooth. Jpn Dent Sci Rev. 2016;52:75–83.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gowans GJ, Bridgers JB, Zhang J, Dronamraju R, Burnetti A, King DA, et al. Recognition of histone crotonylation by Taf14 links metabolic state to gene expression. Mol Cell 2019;76:909–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are indebted to the family who participated in this study. HJB was supported by grants from PRO RETINA Deutschland, Stiftung Auge (Deutsche Ophthalmologische Gesellschaft; HJB), Dr. Senckenbergische Stiftung and Köln Fortune (University Hospital of Cologne).

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Author notes

  1. Hanno J. Bolz

    Present address: Senckenberg Centre for Human Genetics, Dr. Senckenbergische Stiftung, 60314, Frankfurt am Main, Germany

Authors and Affiliations

  1. Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt

    Ghada M. H. Abdel-Salam, Hanan H. Afifi, Mohamed B. Taher & Ghada El-Kamah

  2. Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt

    Mohamed S. Abdel-Hamid

  3. Orodental Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt

    Nermeen E. B. Ahmed

  4. Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany

    Holger Thiele & Peter N. Nürnberg

  5. Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany

    Hanno J. Bolz

Authors
  1. Ghada M. H. Abdel-Salam
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Contributions

GA-S, HA, and HB designed and supervised the study. GA-S, HA, GEl-K, MT were actively involved in clinical evaluation and follow-up of the patient and interpreted the brain MRI. MA-H involved in Sanger sequencing. NA performed the oro-dental examination. HB, HT, PN conducted next-generation sequencing and data analysis and interpretation. The first draft of the paper was written by GA-S. All authors had critically reviewed the paper and approved the final version.

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Correspondence to Ghada M. H. Abdel-Salam.

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Abdel-Salam, G.M.H., Afifi, H.H., Abdel-Hamid, M.S. et al. Expanding the phenotypic spectrum and clinical severity associated with WLS gene. J Hum Genet 68, 607–613 (2023). https://doi.org/10.1038/s10038-023-01152-2

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