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Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis

Nature Genetics volume 41, pages 95–100 (2009)Cite this article

Abstract

Abnormalities in WNT signaling are implicated in a broad range of developmental anomalies and also in tumorigenesis1. Here we demonstrate that germline mutations in WTX (FAM123B), a gene that encodes a repressor of canonical WNT signaling2, cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (OSCS; MIM300373)3. This condition is typically characterized by increased bone density and craniofacial malformations in females and lethality in males. The mouse homolog of WTX is expressed in the fetal skeleton, and alternative splicing implicates plasma membrane localization of WTX as a factor associated with survival in males with OSCS. WTX has also been shown to be somatically inactivated in 11–29% of cases of Wilms tumor4,5,6. Despite being germline for such mutations, individuals with OSCS are not predisposed to tumor development. The observed phenotypic discordance dependent upon whether a mutation is germline or occurs somatically suggests the existence of temporal or spatial constraints on the action of WTX during tumorigenesis.

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Figure 1: Phenotype of the proband (case 06) and delineation of her de novo chromosomal deletion within Xq11.
Figure 2: Functional domains within WTX and alternative splice forms in relation to sites of point mutations associated with OSCS and Wilms tumor.
Figure 3: Expression pattern of Wtx in the E14.5 mouse embryo.
Figure 4: Expression and biochemical properties of the alternatively spliced isoforms of WTX.

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Acknowledgements

The investigators are grateful for the generosity of the individuals and families with OSCS for their participation in this work. Thanks to A. Reeve, J. Matheson and P. Daniel for comments on the manuscript, A. Wilkie and C. Beck for discussions and R. McPhee for assistance with manuscript preparation. S.P.R. is supported by the Child Health Research Foundation of New Zealand and Lotteries Health New Zealand.

Author information

Author notes

  1. Zandra A Jenkins and Margriet van Kogelenberg: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Paediatrics, Dunedin, 9054, New Zealand

    Zandra A Jenkins, Margriet van Kogelenberg, Tim Morgan & Stephen P Robertson

  2. Pathology, Dunedin School of Medicine, Otago University, Dunedin, 9054, New Zealand

    Aaron Jeffs

  3. Department of Biochemistry, Cancer Genetics Laboratory, Dunedin, 9054, New Zealand

    Ryuji Fukuzawa

  4. Department of Zoology, Otago University, Dunedin, 9054, New Zealand

    Esther Pearl

  5. Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Christina Thaller

  6. Division of Craniofacial Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, 98195, Washington, USA

    Anne V Hing

  7. South East Scotland Genetic Service, Western General Hospital, Edinburgh, EH4 2XU, UK

    Mary E Porteous & Sixto Garcia-Miñaur

  8. Institut für Humangenetik, Westfälische Wilhelms-Universität, Münster, D-48149, Germany

    Axel Bohring

  9. Génétique Médicale, CHU de Bordeaux, Université de Bordeaux, Bordeaux, 33800, France

    Didier Lacombe

  10. Department of Medical Genetics, Belfast City Hospital, Belfast, BT9 7AB, Northern Ireland

    Fiona Stewart

  11. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, N-5021, Norway

    Torunn Fiskerstrand & Siren Berland

  12. University of Bergen and Department of Neurology, Institute of Clinical Medicine, Haukeland University Hospital, Bergen, N-5021, Norway

    Laurence Bindoff

  13. Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, 2101, NSW, Australia

    Lesley C Adès & Michel Tchan

  14. Discipline of Paediatrics and Child Health, University of Sydney, Sydney, 2101, NSW, Australia

    Lesley C Adès

  15. Clinical Genetics Department, Nantes University Hospital, Nantes, 44093, France

    Albert David

  16. Clinical and Molecular Genetics Unit, Institute for Child Health, London, WC1N 3JH, UK

    Louise C Wilson & Raoul C M Hennekam

  17. Department of Clinical Genetics, St Mary's Hospital, Manchester, M13 0JH, UK

    Dian Donnai

  18. South West Thames Regional Genetics Unit, St George's Hospital, London, SW17 0RE, UK

    Sahar Mansour

  19. Département de Génétique, Hôpital Necker-Enfants Malades, Paris, 75743, France

    Valérie Cormier-Daire

Authors
  1. Zandra A Jenkins
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  2. Margriet van Kogelenberg
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  25. Stephen P Robertson
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Contributions

Z.A.J. conceived, designed and performed the experiments addressing WTX functions and co-wrote the paper; M.v.K. analysed the microarray data, conceived and performed experiments validating genomic deletions and co-wrote the manuscript; T.M. performed and validated mutation detection; A.J. and R.F. assisted in qPCR and MLPA design and execution; E.P. and C.T. designed and performed the in situ hybridization analysis; A.V.H., M.E.P., S.G.-M., A.B., D.L., F.S., T.F., L.B., S.B., L.C.A., M.T., A.D., L.C.W., R.C.M.H., D.D., S.M. and V.C.-D. ascertained affected individuals, and evaluated and characterized their phenotypes; and S.P.R. led the project, conceived and designed experiments and wrote the paper.

Corresponding author

Correspondence to Stephen P Robertson.

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Competing interests

The corresponding author has filed a provisional patent for the application of insights gained from this study. The patent refers to exploiting the properties of WTX with the aim of improving bone quality and structure.

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Supplementary Figures 1–5, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 956 kb)

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Jenkins, Z., van Kogelenberg, M., Morgan, T. et al. Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet 41, 95–100 (2009). https://doi.org/10.1038/ng.270

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